Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects.

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC0-inf of midazolam was unchanged and the Cmax was reduced by 14%; the AUC0-last of digoxin was increased by 51%, and the Cmax was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer.

Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers.

Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor.

1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC50, 3.55, 12.9, 5.42, 41.6, and 17.2-22.9 µM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 µM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC50, 169 and 55 µM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibition, respectively) at 300 µM. Rucaparib inhibited OCT1, OCT2, MATE1, and MATE2-K (IC50, 4.3, 31, 0.63, and 0.19 µM, respectively).3. DDI risk assessment using static models suggested potential CYP-related DDIs, with rucaparib as a perpetrator. Caution is advised when co-administering rucaparib with sensitive substrates of MATEs, OCT1, and OCT2.

Rociletinib in EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours.

BACKGROUND: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours. METHODS: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles. RESULTS: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml-1 min-1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers. CONCLUSIONS: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.

A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.

AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.

BACKGROUND: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. RESULTS: AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. CONCLUSIONS: AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.

An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic.

Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram-positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function. Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t(1/2)]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values. Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half-lives between 1.2 and 2.4 h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys. Application of the simple allometric equation (Y = aW(b)) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl × BW = aW(b)) resulted in a good correlation between predicted and observed values of Cl, AUC, and t(1/2) in humans. These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans.

Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors.

The phase 1-2 study CO-338-010 (Study 10; NCT01482715) is evaluating single-agent rucaparib, a poly(ADP-ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single-dose and steady-state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40-500 mg; n = 16) or twice daily (BID; dose range, 240-840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half-life was approximately 17 hours, and median time to maximum concentration (tmax ) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady-state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady-state maximum concentration (Cmax ) and area under the concentration-time curve from time zero to 12 hours (AUC0-12h ) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high-fat meal moderately increased rucaparib exposure. The fed-to-fasted geometric mean ratios (90% confidence interval [CI]) for AUC0-24h and Cmax were 138% (117%-162%) and 120% (99.1%-146%); the median (90%CI) tmax delay was 2.5 (0.5-4.4) hours.

Pharmacological analysis of the interaction of antimuscarinic drugs at M(2) and M(3) muscarinic receptors in vivo using the pithed rat assay.

Muscarinic receptor antagonists form the mainstay of the therapeutic options for airway, bladder, and gastrointestinal smooth muscle disorders. Both M(2) and M(3) muscarinic receptors are involved in mediating smooth muscle contractility, although the relative functional contribution of each subtype, especially in the disease state, is unclear. Because the potency and selectivity of compounds for a given receptor in an in vivo setting can be dissimilar to that observed in an in vitro system, we developed an in vivo assay to simultaneously determine the absolute potency and selectivity of muscarinic receptor antagonists at M(2) and M(3) receptors using the pithed rat. Methacholine (MCh)-induced bradycardia and depressor responses were used as surrogate functional endpoints for M(2) and M(3) receptor activation, respectively. The influence of the muscarinic antagonists, tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, or tiotropium on the MCh-induced responses were studied. The estimated DR(10) values (dose producing a tenfold shift in the MCh curve) of tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, and tiotropium for the M(2) muscarinic receptor-mediated bradycardia were 0.22, 1.18, approximately 2.6, 0.025, 0.40, and 0.0026 mg/kg, respectively, and 0.14, 0.18, 0.11, 3.0, 0.18, and 0.0017 mg/kg, respectively, for the M(3) muscarinic receptor-mediated depressor response. In a separate set of experiments, a single intravenous dose of tiotropium was administered before a MCh curve at 1, 3, 6, or 9 h to determine if tiotropium exhibited time-dependent selectivity for the M(3) receptor as has been reported from in vitro studies. The results indicate a slight preference of tiotropium for the M(3) receptor at later time points. The pithed rat assay may serve useful for elucidating the functional contribution of M(2) and M(3) receptors to the in vivo pharmacological effects of antagonists in disease animal models.

Discovery of (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (TD-5959, GSK961081, batefenterol): first-in-class dual pharmacology multivalent muscarinic antagonist and ß2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD).

Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and ß2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in a guinea pig bronchoprotection model. Concomitantly we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.

UNLABELLED: Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the fi rst drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR.

Metabolism, pharmacokinetics, and excretion of a highly selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in human cytochrome P450 2D6 extensive and poor metabolizers.

The excretion, biotransformation, and pharmacokinetics of a selective N-methyl-D-aspartate receptor antagonist, traxoprodil, were investigated in six healthy male volunteers, phenotyped either as CYP2D6 extensive or poor metabolizers of dextromethorphan. Each subject received an i.v. infusion of a single 50-mg (100 microCi) dose of [(14)C]traxoprodil. Approximately 89% of the administered dose was recovered in poor metabolizers (PMs) and 61% in extensive metabolizers (EMs), with the majority of the dose being excreted in the urine (86% in PMs and 52% in EMs). The elimination of traxoprodil was more rapid in EMs than in PMs with terminal elimination half-lives of 2.8 and 26.9 h, respectively, for EMs and PMs. Area under the plasma concentration-time curve from time 0 to T (AUC((0-Tlast))) values for unchanged traxoprodil were 1.2 and 32.7% of the corresponding AUC values for total radioactivity in EMs and PMs, respectively. Traxoprodil was metabolized in both EMs and PMs, with approximately 7 and 50% of the administered radioactivity excreted as unchanged drug in the excreta of EMs and PMs, respectively. Hydroxylation at the 3-position of the hydroxyphenyl ring and methylation of the resulting catechol followed by conjugation were identified as the main metabolic pathways in EMs. In contrast, direct conjugation of traxoprodil with glucuronic or sulfuric acid was the major pathway in PMs. In vitro studies using CYP2D6-selective inhibitor and recombinant enzyme also support that the metabolism of traxoprodil is mainly mediated by CYP2D6. Taken together, these studies suggest that traxoprodil is eliminated mainly by Phase I oxidative metabolism mediated by CYP2D6 isozyme in EMs and by Phase II conjugation and renal clearance of parent in PMs.