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Administration of long-acting injectable suspensions is an increasingly common approach to increasing patient compliance and improving therapeutic efficacy through less frequent dosing. While several long-acting suspensions have recently been marketed, parameters modulating drug absorption from suspension-based formulations are not well understood. Further, methods for predicting clinical pharmacokinetic data from preclinical studies are not well established. Together, these limitations hamper compound selection, formulation design and formulation selection through heavy reliance on iterative optimization in preclinical and clinical studies. This article identifies key parameters influencing absorption from suspension-based formulations through compilation and analysis of preclinical and clinical pharmacokinetic data of seven compounds marketed as suspensions; achievable margins for predicting the clinical dose and input rate from preclinical studies as a function of the preclinical species, the clinical injection location and the intended therapeutic duration were also established.
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Suspensiones , Humanos , Estudios Retrospectivos , InyeccionesRESUMEN
PURPOSE: This work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation. METHODS: PK-PD analysis was applied to data from a functional magnetic resonance imaging (fMRI) technique to non-invasively measure treatment mediated inhibition of olfaction signaling in non-human primates (NHPs). Initial exposure-response was evaluated using single time point data pooled across 27 compounds to inform on in vitro to in vivo correlation (IVIVC). More robust effect compartment PK-PD modeling was conducted for a subset of 10 compounds with additional PD and PK data to characterize hysteresis. RESULTS: The pooled compound exposure-response facilitated an early exploration of IVIVC with a limited dataset for each individual compound, and it suggested a 2.4-fold in vitro to in vivo scaling factor for the NaV1.7 target. Accounting for hysteresis with an effect compartment PK-PD model as compounds advanced towards preclinical development provided a more robust determination of in vivo potency values, which resulted in a statistically significant positive IVIVC with a slope of 1.057 ± 0.210, R-squared of 0.7831, and p value of 0.006. Subsequent simulations with the PK-PD model informed the design of anti-nociception efficacy studies in NHPs. CONCLUSIONS: A staged approach to PK-PD modeling and simulation enabled integration of in vitro NaV1.7 potency, plasma protein binding, and pharmacokinetics to describe the exposure-response profile and inform future study design as the NaV1.7 inhibitor effort progressed through drug discovery.
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Canal de Sodio Activado por Voltaje NAV1.7/química , Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Algoritmos , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Circulación Cerebrovascular , Diseño de Fármacos , Descubrimiento de Drogas , Células HEK293 , Humanos , Técnicas In Vitro , Macaca mulatta , Imagen por Resonancia Magnética , Modelos Biológicos , Olfato/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
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Descubrimiento de Drogas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Perros , Humanos , Ratones , Ratas , Administración Oral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Relación Estructura-ActividadRESUMEN
Studies have shown that some peptides and small molecules can induce non IgE-mediated anaphylactoid reactions through mast cell activation. Upon activation, mast cells degranulate and release vasoactive and proinflammatory mediators, from cytoplasmic granules into the extracellular environment which can induce a cascade of severe adverse reactions. This study describes a lead optimization strategy to select NaV1.7 inhibitor peptides that minimize acute mast cell degranulation (MCD) toxicities. Various in vitro, in vivo, and PKPD models were used to screen candidates and guide peptide chemical modifications to mitigate this risk. Anesthetized rats dosed with peptides demonstrated treatment-related decreases in blood pressure and increases in plasma histamine concentrations which were reversible with a mast cell stabilizer, supporting the MCD mechanism. In vitro testing in rat mast cells with NaV1.7 peptides demonstrated a concentration-dependent increase in histamine. Pharmacodynamic modeling facilitated establishing an in vitro to in vivo correlation for histamine as a biomarker for blood pressure decline via the MCD mechanism. These models enabled assessment of structure-activity relationship (SAR) to identify substructures that contribute to peptide-mediated MCD. Peptides with hydrophobic and cationic characteristics were determined to have an elevated risk for MCD, which could be reduced or avoided by incorporating anionic residues into the protoxin II scaffold. Our analyses support that in vitro MCD assessment in combination with PKPD modeling can guide SAR to improve peptide lead optimization and ensure an acceptable early in vivo tolerability profile with reduced resources, cycle time, and animal use.
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Mastocitos , Drogas Sintéticas , Animales , Degranulación de la Célula , Plomo , Mastocitos/metabolismo , Péptidos/química , Péptidos/toxicidad , Ratas , Drogas Sintéticas/metabolismoRESUMEN
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.
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Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Venenos de Araña/síntesis química , Animales , Degranulación de la Célula/efectos de los fármacos , Cistina/química , Diseño de Fármacos , Calor , Mastocitos/efectos de los fármacos , Modelos Moleculares , Dimensión del Dolor/efectos de los fármacos , Ratas , Venenos de Araña/farmacologíaRESUMEN
A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.
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Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Animales , Ratones , Ratas , Ratas WistarRESUMEN
Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacocinética , Modelos Teóricos , Latencia del Virus/efectos de los fármacos , Automatización de Laboratorios , Técnicas de Cultivo de Célula , Células Cultivadas , Regulación Viral de la Expresión Génica/efectos de los fármacos , VIH/genética , Humanos , Células Jurkat , Replicación Viral/efectos de los fármacosRESUMEN
MK-2075 is a small-molecule selective inhibitor of the NaV1.7 channel investigated for the treatment of postoperative pain. A translational strategy was developed for MK-2075 to quantitatively interrelate drug exposure, target modulation, and the desired pharmacological response in preclinical animal models for the purpose of human translation. Analgesics used as a standard of care in postoperative pain were evaluated in preclinical animal models of nociceptive behavior (mouse tail flick latency and rhesus thermode heat withdrawal) to determine the magnitude of pharmacodynamic (PD) response at plasma concentrations associated with efficacy in the clinic. MK-2075 was evaluated in those same animal models to determine the concentration of MK-2075 required to achieve the desired level of response. Translation of MK-2075 efficacious concentrations in preclinical animal models to a clinical PKPD target in humans was achieved by accounting for species differences in plasma protein binding and in vitro potency against the NaV1.7 channel. Estimates of human pharmacokinetic (PK) parameters were obtained from allometric scaling of a PK model from preclinical species and used to predict the dose required to achieve the clinical exposure. MK-2075 exposure-response in a preclinical target modulation assay (rhesus olfaction) was characterized using a computational PKPD model which included a biophase compartment to account for the observed hysteresis. Translation of this model to humans was accomplished by correcting for species differences in PK NaV1.7 potency, and plasma protein binding while assuming that the kinetics of distribution to the target site is the same between humans and rhesus monkeys. This enabled prediction of the level of target modulation anticipated to be achieved over the dosing interval at the projected clinical efficacious human dose. Integration of these efforts into the early development plan informed clinical study design and decision criteria.
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Hematopoietic progenitor kinase 1 (HPK1), also referred to as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a serine/threonine kinase that negatively regulates T-cell signaling by phosphorylating Ser376 of Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76), a critical mediator of T-cell receptor activation. HPK1 loss of function mouse models demonstrated enhanced immune cell activation and beneficial antitumor activity. To enable discovery and functional characterization of high-affinity small-molecule HPK1 inhibitors, we have established high-throughput biochemical, cell-based, and novel pharmacodynamic (PD) assays. Kinase activity-based time-resolved fluorescence energy transfer (TR-FRET) assays were established as the primary biochemical approach to screen for potent inhibitors and assess selectivity against members of MAP4K and other closely related kinases. A proximal target engagement (TE) assay quantifying pSLP-76 levels as a readout and a distal assay measuring IL-2 secretion as a functional response were established using human peripheral blood mononuclear cells (PBMCs) from two healthy donors. Significant correlations between biochemical and cellular assays as well as excellent correlation between the two donors for the cellular assays were observed. pSLP-76 levels were further used as a PD marker in the preclinical murine model. This effort required the development of a novel ultrasensitive single-molecule array (SiMoA) assay to monitor pSLP-76 changes in mouse spleen.
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Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Animales , Línea Celular , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.
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Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
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Canal de Sodio Activado por Voltaje NAV1.7 , Dolor , Animales , Humanos , Macaca mulatta , Nocicepción , NociceptoresRESUMEN
Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).
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The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.
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Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Quinazolinonas/química , Quinazolinonas/farmacología , Animales , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Cromatografía Líquida de Alta Presión , Descubrimiento de Drogas , Haplorrinos , Humanos , Quinazolinonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/farmacocinética , Humanos , Macaca mulatta , Masculino , Células PC12 , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tauopatías/tratamiento farmacológico , beta-N-Acetilhexosaminidasas/química , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
INTRODUCTION: The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates. METHODS: In this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting. RESULTS: Clinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect. CONCLUSION: We propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics.
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This open-label 2-period study assessed the effect of multiple-dose administration of rifampin, a strong cytochrome P450 3A (CYP3A) and P-glycoprotein inducer, on the pharmacokinetics of odanacatib, a cathepsin K inhibitor. In period 1, 12 healthy male subjects (mean age, 30 years) received a single dose of odanacatib 50 mg on day 1, followed by a 28-day washout. In period 2, subjects received rifampin 600 mg/day for 28 days; odanacatib 50 mg was coadministered on day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and on day 1 of period 1 and day 14 of period 2. Coadministration of odanacatib and rifampin significantly reduced odanacatib exposure. The odanacatib AUC0-∞ geometric mean ratio (90% confidence interval) of odanacatib + rifampin/odanacatib alone was 0.13 (0.11-0.16). The harmonic mean ± jackknife standard deviation apparent terminal half-life (t½ ) was 71.6 ± 10.2 hours for odanacatib alone and 16.0 ± 3.4 hours for odanacatib + rifampin, indicating greater odanacatib clearance following coadministration with rifampin. Samples were collected in period 2 during rifampin dosing (days 1, 14, and 28) and after rifampin discontinuation (days 35, 42, and 56) to evaluate the ratio of plasma 4ß-hydroxycholesterol to total serum cholesterol as a CYP3A4 induction biomarker; the ratio increased â¼5-fold over 28 days of daily dosing with 600 mg rifampin, demonstrating sensitivity to CYP3A4 induction.
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Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/sangre , Rifampin/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/sangre , Adulto , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas/fisiología , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.
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A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
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Herein, we describe the development of a functionally selective liver X receptor ß (LXRß) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-ß peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/líquido cefalorraquídeo , Benzamidas/química , Benzamidas/farmacología , Receptores Nucleares Huérfanos/agonistas , Piperidinas/química , Piperidinas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Células Hep G2 , Humanos , Lípidos/análisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Locomoción/efectos de los fármacos , Macaca mulatta , Células de Riñón Canino Madin Darby , Ratones , Ratones TransgénicosRESUMEN
We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2 mg was administered (Day -1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2 mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC(0- ∞) GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC(0-∞) GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day -1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg.