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PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.
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The United States continues to be impacted by decades of an opioid misuse epidemic, worsened by the COVID-19 pandemic and by the growing prevalence of highly potent synthetic opioids (HPSO) such as fentanyl. In instances of a toxicity event, first-response administration of reversal medications such as naloxone can be insufficient to fully counteract the effects of HPSO, particularly when there is co-occurring substance use. In an effort to characterize and study this multi-faceted problem, the Camden Opioid Research Initiative (CORI) has been formed. The CORI study has collected and analyzed post-mortem toxicology data from 42 cases of decedents who expired from opioid-related toxicity in the South New Jersey region to characterize substance use profiles. Co-occurring substance use, whether by intent or through possible contamination of the illicit opioid supply, is pervasive among deaths due to opioid toxicity, and evidence of medication-assisted treatment is scarce. Nearly all (98%) of the toxicology cases show the presence of the HPSO, fentanyl, and very few (7%) results detected evidence of medication-assisted treatment for opioid use disorder, such as buprenorphine or methadone, at the time of death. The opioid toxicity reversal drug, naloxone, was detected in 19% of cases, but 100% of cases expressed one or more stimulants, and sedatives including xylazine were detected in 48% of cases. These results showing complex substance use profiles indicate that efforts at mitigating the opioid misuse epidemic must address the complications presented by co-occurring stimulant and other substance use, and reduce barriers to and stigmas of seeking effective medication-assisted treatments.
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Overdose de Drogas , Transtornos Relacionados ao Uso de Opioides , Humanos , Estados Unidos , Analgésicos Opioides/efeitos adversos , Pandemias , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Fentanila/efeitos adversos , Naloxona/uso terapêutico , Overdose de Drogas/epidemiologiaRESUMO
This pilot study assessed the safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794), a genetically modified autologous T-cell therapy targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1 isoform A (LAGE-1a)-positive myeloma cells, alone or in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma. Eligible patients expressed NY-ESO-1 and/or LAGE-1a and either HLA-A∗02:01, ∗02:05, or ∗02:06. Patients received lete-cel single infusion alone (arm 1) or with pembrolizumab (arm 2). 127 patients were screened, and 6 patients (3 per arm) were enrolled; patients in arm 1 and 2 received lete-cel alone, or with pembrolizumab, respectively. All patients exhibited grade 3/4 cytopenias, which resolved or improved to grade 1. One patient (arm 1) had grade 3/4 lete-cel-related adverse events (AEs); 2 patients (arm 2) had grade 3/4 AEs related to lete-cel and lymphodepletion. Three patients with grade 1/2 cytokine release syndrome (CRS) exhibited elevated post-lete-cel interleukin-6 levels versus those without CRS. Pooled overall response rate was 50% including 1 patient each with confirmed clinical response, very good clinical response, and partial response, and progression-free survival ranged from 1.3 to 5.2 months. Responders (arm 1: n = 1; arm 2: n = 2) had a time-to-response of 3 weeks, duration of response of 2.1 months. Two responders, but no nonresponders, exhibited elevated cytokine levels after lete-cel infusion. Lete-cel had a manageable safety profile and demonstrated clear but transient antitumor activity in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT03168438.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Projetos PilotoRESUMO
Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care. Our results further support the potential for CYP2D6 PGx testing to inform chronic pain medication management for poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Future efforts to implement PGx testing in chronic pain management, however, must address patient concerns about genetic test result access and genetic discrimination.
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Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
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Sarcoma Sinovial , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Sarcoma Sinovial/terapia , Microambiente TumoralRESUMO
PURPOSE: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). METHODS: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. RESULTS: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. CONCLUSION: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. TRIAL REGISTRATION: NCT03359850; registered December 2, 2017.
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Indazóis/efeitos adversos , Indazóis/farmacocinética , Fígado/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Idoso , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/sangueRESUMO
BACKGROUND: The opioid use disorder and overdose crisis in the United States affects public health as well as social and economic welfare. While several genetic and non-genetic risk factors for opioid use disorder have been identified, many of the genetic associations have not been independently replicated, and it is not well understood how these factors interact. This study is designed to evaluate relationships among these factors prospectively to develop future interventions to help prevent or treat opioid use disorder. METHODS: The Genomics of Opioid Addiction Longitudinal Study (GOALS) is a prospective observational study assessing the interplay of genetic and non-genetic by collecting comprehensive genetic and non-genetic information on 400 participants receiving medication for opioid use disorder. Participants will be assessed at four time points over 1 year. A saliva sample will be collected for large-scale genetic data analyses. Non-genetic assessments include validated surveys measuring addiction severity, depression, anxiety, and adverse childhood experiences, as well as treatment outcomes such as urine toxicology results, visit frequency, and number of pre and post-treatment overdoses extracted from electronic medical records. DISCUSSION: We will use these complex data to investigate the relative contributions of genetic and non-genetic risk factors to opioid use disorder and related treatment outcomes.
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Transtornos Relacionados ao Uso de Opioides , Adulto , Genômica , Humanos , Estudos Longitudinais , Masculino , Estados UnidosRESUMO
To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).
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Compostos de Bifenilo/farmacocinética , Conservadores da Densidade Óssea/farmacocinética , Reabsorção Óssea/prevenção & controle , Catepsina K/antagonistas & inibidores , Adulto , Idoso , Biomarcadores/urina , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Reabsorção Óssea/diagnóstico , Reabsorção Óssea/urina , Catepsina K/metabolismo , Creatinina/urina , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/urina , Pró-Colágeno/urina , Resultado do Tratamento , Adulto JovemRESUMO
This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.
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Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacocinética , Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/farmacocinética , Catepsina K/antagonistas & inibidores , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/uso terapêutico , Índice de Massa Corporal , Peso Corporal , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Ensaios Clínicos como Assunto , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Relação Dose-Resposta a Droga , Vias de Eliminação de Fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Fatores Raciais , Insuficiência RenalRESUMO
Bezlotoxumab is a monoclonal antibody approved for the prevention of recurrent Clostridium difficile infection (rCDI). In a previous exposure-response (E-R) analysis of bezlotoxumab exposure and rCDI, based on data from two phase 3 trials in participants who received placebo or bezlotoxumab 10 mg/kg, rCDI was treated as a binary endpoint and discontinued subjects were imputed as not having rCDI, resulting in an apparent positive E-R trend between rCDI rates and bezlotoxumab exposure. Therefore, a time-to-event (TTE) analysis was applied to investigate the E-R relationship, accounting for the time to rCDI occurrence and participant discontinuation. A TTE model, applying a time-dependent hazard function and right-censoring of data based on rCDI, discontinuation, or study end was developed. Exposure effects and covariates effects were evaluated as predictors affecting the hazard. The TTE model consisted of a Gompertz function with age, endogenous immunoglobulin G to C. difficile toxin B (IgG-B), history of CDI, hospitalization, sex, Charlson Comorbidity Index, and concomitant use of systemic antibiotics affecting the hazard. Exposure effects were characterized with a maximum effect (Emax) E-R relationship on the baseline parameter, and bezlotoxumab exposures achieved at the 10 mg/kg dose were found to be on the plateau of the E-R curve. Endogenous IgG-B significantly impacted the Emax, indicating that low-titer participants derive a greater benefit from bezlotoxumab treatment compared with high-titer participants. The results support the conclusions of the previous E-R analysis, where exposures achieved at the 10 mg/kg dose are on the plateau of the E-R curve.
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Amplamente Neutralizantes/uso terapêutico , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Adulto , Idoso , Envelhecimento , Anticorpos Monoclonais/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Imunoglobulina G/análise , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Recidiva , Caracteres Sexuais , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: the effects of obesity on health are a concern for the military as they affect the fitness to serve of active service members, increase costs to the Military Health System, and reduce quality of life for veterans and beneficiaries. Although obesity can be influenced by behavioral and environmental factors, it has also been shown to be associated with genetic risk factors that are not fully understood. MATERIALS AND METHODS: we performed a genome-wide association study of 5,251 participants in the Coriell Personalized Medicine Collaborative, which includes 2,111 Air Force participants. We applied a generalized linear model, using principal component analysis to account for population structure, and analyzed single-variant associations with body mass index (BMI) as a continuous variable, using a Bonferroni-corrected P-value threshold to account for multiplicity. RESULTS: we identified one genome-wide significant locus, rs11670527, upstream of the ZNF264 gene on chromosome 19, associated with BMI. CONCLUSIONS: the finding of an association between rs11670527 and BMI adds to the growing body of literature characterizing the complex genetics of obesity. These efforts may eventually inform personalized interventions aimed at achieving and maintaining healthy weight.
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Índice de Massa Corporal , Militares/estatística & dados numéricos , Obesidade/genética , Adulto , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Obesidade/epidemiologia , Ohio/epidemiologia , Medicina de Precisão/instrumentação , Medicina de Precisão/métodosRESUMO
Assessing risk for QTc interval prolongation in a thorough QTc study is a standard recommendation when evaluating new chemical entities. As part of the clinical development program for odanacatib, an oral selective inhibitor of cathepsin K previously in development for the treatment of osteoporosis, 2 clinical studies in healthy subjects assessed pharmacokinetics and overall safety (including potential for delayed ventricular repolarization) of a supratherapeutic dose. In study 1, subjects received a supratherapeutic dose regimen of odanacatib (300 mg on day 1, then daily multiple doses of 25 mg to day 21) or placebo. In study 2 (days 1-4), subjects received the odanacatib supratherapeutic dose regimen or moxifloxacin (positive control, single 400-mg dose on day 4; matching placebo for odanacatib/moxifloxacin) or placebo. All doses were administered with a high-fat meal. In study 1 (N = 12), the supratherapeutic dosing regimen achieved exposure â¼3.5-fold of the proposed therapeutic dose (50 mg once weekly) and was sufficiently well tolerated to permit assessment in the thorough QTc study (study 2). In study 2 (N = 116), the primary objective was placebo-corrected change from baseline in QTcF interval (Fridericia's correction), assessed by replicate electrocardiograms (12-lead Holter recordings; days -1 through 7). Supratherapeutic odanacatib dosing was not associated with increased risk of prolonged QT interval, unlike moxifloxacin (confirming assay sensitivity). Pooled safety data across both studies suggested that the safety profile of odanacatib at high exposures was similar to placebo, with a small clustering of oral cavity adverse events. Odanacatib was not associated with increased risk of prolonged QT interval.
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Compostos de Bifenilo/administração & dosagem , Eletrocardiografia Ambulatorial/métodos , Síndrome do QT Longo/diagnóstico , Moxifloxacina/administração & dosagem , Adulto , Compostos de Bifenilo/efeitos adversos , Catepsina K/antagonistas & inibidores , Relação Dose-Resposta a Droga , Método Duplo-Cego , Cálculos da Dosagem de Medicamento , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/induzido quimicamente , Masculino , Margens de Excisão , Moxifloxacina/efeitos adversos , Adulto JovemRESUMO
Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 µM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.
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Compostos de Bifenilo/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacocinética , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacocinética , Osso e Ossos/enzimologia , Osso e Ossos/fisiopatologia , Catepsina K/metabolismo , Inibidores de Cisteína Proteinase/efeitos adversos , Inibidores de Cisteína Proteinase/farmacocinética , Feminino , Humanos , Masculino , Osteoporose/enzimologia , Osteoporose/patologia , Transdução de Sinais , Pesquisa Translacional Biomédica , Resultado do TratamentoRESUMO
OBJECTIVES: The objectives of this study were to determine whether differences in CYP2C8 and CYP2C9 haplotype influence the dose of ibuprofen self-administered by individuals, and to examine the potential relationship between CYP2C8 and CYP2C9 reduced metabolism haplotypes and adverse events. PARTICIPANTS AND METHODS: We investigated relationships between genetic variations in CYP2C8 and CYP2C9 and ibuprofen use, dose, and side effects (reported by questionnaire) in 445 participants from the Coriell Personalized Medicine Collaborative. RESULTS: Carriers of reduced metabolism haplotypes for CYP2C8 (*2, *3, *4) and CYP2C9 (*2, *3) were significantly (P=0.0171) more likely than those lacking these variants to take less than the recommended dose of ibuprofen, after controlling for sex, age, race, and cohort. In contrast to ibuprofen dose, there were no differences in ibuprofen use frequency or reported side effects based on haplotype. However, there are often no early signs of acute kidney injury, the most serious side effect of elevated ibuprofen exposure. CONCLUSION: These results suggest a subset of individuals with genetic variation in CYP2C8 and CYP2C9 recognize that they obtain adequate drug efficacy with lower ibuprofen doses, or take lower doses due to prior side effects. However, most (82.6%) individuals with reduced metabolism haplotypes nonetheless took recommended or higher doses, potentially putting them at increased risk for side effects.
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Injúria Renal Aguda/genética , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Ibuprofeno/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Adulto , Idoso , Feminino , Genótipo , Haplótipos/genética , Heterozigoto , Humanos , Ibuprofeno/efeitos adversos , Inativação Metabólica/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Medicina de PrecisãoRESUMO
Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women received single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration-time profile (AUC0-168h ) and maximum plasma concentration (Cmax ) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks. Median time to Cmax (tmax ) was 3 and 4 hours following single- and multiple-dose administration, respectively. The arithmetic mean ± SD terminal half-life was 81.0 ± 14.0 and 106.7 ± 14.4 hours following single- and multiple-dose administration, respectively. Comparison of multiple-dose PK parameters showed that the geometric mean ratios (Chinese/non-Chinese) and 95%CIs for AUC0-168h and Cmax were 0.81 (0.55-1.19) and 0.87 (0.69-1.11), respectively. All adverse events were mild, none were serious, and none led to discontinuation. Single- and multiple-dose PKs of ODN 50 mg in Chinese postmenopausal women were generally similar to those previously reported in non-Chinese postmenopausal women.
Assuntos
Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Pós-Menopausa/sangue , Administração Oral , Idoso , Área Sob a Curva , Povo Asiático , Compostos de Bifenilo/efeitos adversos , Esquema de Medicação , Drogas em Investigação , Feminino , Meia-Vida , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/etnologiaRESUMO
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.
Assuntos
Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Rifampina/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Adulto , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Esquema de Medicação , Interações Medicamentosas/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was â¼100 liters. The clearance was â¼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.
Assuntos
Compostos de Bifenilo/farmacocinética , Interações Alimento-Droga , Pós-Menopausa , Administração Oral , Idoso , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: This study was designed to demonstrate that alendronate (ALN)/vitamin D3 combination tablets (ALN/D5600) are bioequivalent to corresponding doses of ALN and vitamin D3 as individual tablets in healthy Taiwanese volunteers. METHODS: In this open-label, randomized, 2-period, crossover study, 68 volunteers were randomized to a single ALN/D5600 combination tablet or corresponding doses of 70 mg ALN + 5600 IU vitamin D3 (2 × 2800 IU), followed by a 12-day washout period and administration of the alternate formulation. Plasma ALN levels were measured using a newly developed assay. Geometric mean ratios of ALN AUC0-last, AUC0-∞, and Cmax, and unadjusted vitamin D3 AUC0-80h and Cmax were compared and considered bioequivalent if the 90% CI was within 0.8 to 1.25. RESULTS: The geometric mean ratios were: AUC0-last, 1.084 (90% CI, 0.937-1.253); AUC0-∞, 1.081 (90% CI, 0.935-1.249); and Cmax, 1.112 (90% CI, 0.959-1.289) for ALN, and AUC0-80h 0.953 (90% CI, 0.827-1.098) and Cmax, 0.982 (90% CI, 0.854-1.130) for vitamin D3 unadjusted for endogenous levels. CONCLUSIONS: The combination tablet was considered bioequivalent to coadministration based on ALN AUC0-∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0-last and Cmax (upper 90% CIs outside the bounds) were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.
RESUMO
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.
Assuntos
Adjuvantes Anestésicos/farmacocinética , Anti-Inflamatórios/farmacocinética , Compostos de Bifenilo/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Prednisona/farmacocinética , Adjuvantes Anestésicos/administração & dosagem , Adulto , Anti-Inflamatórios/administração & dosagem , Área Sob a Curva , Compostos de Bifenilo/administração & dosagem , Interações Medicamentosas , Meia-Vida , Humanos , Masculino , Midazolam/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Adulto JovemRESUMO
Odanacatib is a selective inhibitor of the cathepsin K enzyme that is expressed in osteoclasts involved in the degradation of bone organic matrix, and is being developed as a novel treatment of osteoporosis. Odanacatib has demonstrated increases in bone mineral density in postmenopausal women and is undergoing a pivotal phase III trial. The absorption, metabolism, and excretion of [(14)C]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 µCi). Plasma, urine, and fecal samples were collected at intervals up to 34 days postdose. The pharmacokinetics of odanacatib were characterized by slow absorption (mean time to achieve maximum plasma concentration of 14.2 hours) and long apparent elimination half-life (mean t1/2 96.7 hours); 74.5% of the dose was recovered in feces and 16.9% in urine, resulting in a total recovery of 91.4%. Seven metabolites were identified in urine; the major pathway (methyl hydroxylation producing M8 and its derivatives) was largely dependent on CYP3A. Metabolites and odanacatib accounted for 77% and 23% of urinary radioactivity, respectively. In fecal extracts, the only radioactive components identified were odanacatib (60.9%) and M8 (9.5%). The fraction of odanacatib in feces derived from absorbed drug was estimated using a bioavailability value obtained from the results of a separate intravenous study. Collectively, the data indicate that odanacatib has a long t1/2 on account of its low metabolic intrinsic clearance, and that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for â¼70% and â¼30% of the clearance of odanacatib in humans.