Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40-102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5-to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial Registration ClinicalTrials.gov (NCT02073994).
Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae. The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (Cmax) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.)
INTRODUCTION: Somatic IDH1/2 mutations occur in multiple solid and hematologic tumors, including acute myeloid leukemia. Mutant IDH1/2 proteins have novel enzymatic activity, catalyzing the reduction of α-ketoglutarate to produce the oncometabolite, D-2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes including impaired cellular differentiation. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of the mutated IDH1 protein, and has been shown to lower 2-HG levels and restore cellular differentiation in IDH1-mutant primary human blast cells cultured ex vivo. AG-120 is currently being assessed in a first-in-human, phase 1 study enrolling patients with IDH1-mutant, advanced hematologic malignancies (NCT02074839). Our objective was to further assess the longitudinal pharmacokinetic/pharmacodynamic (PK/PD) data from the ongoing phase 1 study, including dose proportionality assessment of AG-120 exposure after single and multiple doses over time, and the influence of patient-intrinsic factors. METHODS: The AG-120 phase 1, open-label, dose-escalation and expansion study includes evaluation of safety, tolerability, maximum tolerated dose, PK/PD (including 2-HG levels) and clinical activity. Single-agent AG-120 is administered orally once (QD) or twice (BID) daily in continuous 28-day cycles. Patients included in this analysis received doses of 100 mg BID, 300 mg QD, 500 mg QD, 800 mg QD and 1200 mg QD (N=39). Blood, bone marrow and urine samples were collected at multiple time points for determination of PK/PD using qualified LC-MS/MS-based methods. Analyses were performed using WinNonLin®. RESULTS: AG-120 exposure exceeding the predicted efficacious exposure level was demonstrated at all dose levels following oral administration. Following both single (Day-3) and multiple (Cycle 1 Day 15 [C1D15] and Cycle 2 Day 1) dose administration, mean plasma exposures of AG-120 increased less than proportionally to dose, although plasma exposures were quite variable within dose levels. Preliminary PK data revealed a mean half-life of 119 ± 104 hr. Following multiple doses, most patients achieved steady state in Cycle 1, with ~2 to 3-fold accumulation in plasma observed. Furthermore, pre-dose AG-120 trough levels were maintained above the predicted efficacious exposure level throughout treatment (up to 11 cycles). Following a single dose of AG-120, plasma 2-HG levels gradually reduced over 3 days. After multiple doses, plasma 2-HG levels were reduced to levels seen in healthy volunteers (up to 99.7% inhibition) at all dose levels tested. Steady state 2-HG inhibition was reached at approximately C1D15 in most patients, and was maintained over the course of treatment (up to 11 cycles). Mean bone marrow 2-HG levels were also substantially reduced following multiple doses of AG-120 at all dose levels tested (up to 99.9% reduction compared with baseline). Plasma 2-HG levels showed a positive correlation with levels in bone marrow (r2=0.882, p<0.001) and urine (r2=0.528, p<0.001), with a stronger correlation being observed with the former tissue. There was no clear effect of patient-intrinsic factors such as body weight or body surface area on Cmaxor AUC within the ranges tested, although the current sample size is small. Population PK and PK/PD assessments will be conducted to confirm these findings. These analyses are based on data as of 1 May 2015; updated analyses will be presented. CONCLUSION: AG-120 exposure increased less than proportionally to dose following oral administration, with long half-life and maintenance of pre-dose levels above the predicted efficacious exposure, supporting QD dosing. In patients with IDH1 mutations, AG-120 inhibited plasma 2-HG to within levels found in healthy volunteers, and also inhibited 2-HG in bone marrow. Disclosures Fan: Agios Pharmaceuticals: Employment, Equity Ownership. Le:Agios Pharmceuticals: Employment, Equity Ownership. Manyak:Agios Pharmaceuticals: Employment. Liu:Agios: Employment. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals: Employment. Biller:Agios Pharmaceuticals: Employment, Equity Ownership; Arbutus BioPharma (formerly Tekmira): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Arvinas: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Denali: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Agresta:Agios: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership.
A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design. KEYWORDS: Pseudomonas aeruginosa, β-lactam, penicillin binding protein, siderophore, monocarbam, structure-guided design O ne of the largest challenges in the discovery of new Gram-negative antibacterial agents is the identification of chemotypes that can penetrate the cell envelope. 1 The pathogens, such as Pseudomonas aeruginosa (P. aeruginosa), have evolved complex cell architectures including an outer membrane composed of charged lipopolysaccharides, a thin peptidogylcan layer, and an inner membrane made up of phospholipids. 2 Identifying molecules with the necessary features to enable permeation has been a challenge.β-Lactams are one chemotype that have been successful in the treatment of P. aeruginosa. 3 Since the discovery of penicillin, β-lactams have been used in the clinic and are still widely prescribed. One of the most effective classes of β-lactams for the treatment of P. aeruginosa infections are the carbapenems (e.g., meropenem, 1, Figure 1). 4 Their effectiveness stems from their ability to acylate their penicillin-binding protein (PBP) targets, aided by high permeability into P. aeruginosa through the outer membrane porins. 5 However, they are currently being challenged in the clinic by the increasing emergence of broadspectrum serine β-lactamases and metallo-β-lactamases which hydrolyze most β-lactams and render them ineffective. 6 There is one class of β-lactams that is stable to the metallo-β-lactamases: the monocyclic β-lactams represented by aztreonam (2). Aztreonam however has limited effectiveness against P. aeruginosa presumably due to its poor permeation of the outer membrane, β-lactamase susceptibility, and high propensity for efflux (P. aeruginosa MIC 90 ≥ 1024 μg/mL, n = 20 panel). 3,7 To address the poor activity of 2, we focused on improving permeation by introducing siderophore mimics to promote uptake. 8−10 Siderophores are small Fe-chelating molecules synthesized and secreted by bacteria to scavenge iron from the host. 9,11 The iron-complexed siderophores are then brought into the cell via the iron uptake machinery, enabling the bacteria to access the much needed nutrient. It has been shown that introduction of iron-chelating groups to a monocyclic β-lactam scaffold ca...
SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.
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