RESUMO
AIM: Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months. METHODS: An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF. RESULTS: Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie, >24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo. CONCLUSION: The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient.
Assuntos
Hormônio Liberador de Gonadotropina , Leiomioma , Humanos , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Leiomioma/tratamento farmacológico , Leiomioma/induzido quimicamente , Leiomioma/complicações , Hidrocarbonetos Fluorados/efeitos adversos , Densidade Óssea , Desenvolvimento de MedicamentosRESUMO
The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of â¼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8-1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.
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Modelos Biológicos , Administração Oral , Ensaios Clínicos Fase III como Assunto , Simulação por Computador , Liberação Controlada de Fármacos , Hidrocarbonetos Fluorados , Pirimidinas , Solubilidade , Equivalência TerapêuticaRESUMO
Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need. Herein, we describe the rationale and design of the first study of venetoclax in pediatric patients with relapsed/refractory malignancies: a Phase I trial investigating the safety and pharmacokinetics of venetoclax monotherapy followed by the addition of chemotherapy (Trial registration: EudraCT 2017-000439-14; NCT03236857).
Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Protocolos Clínicos , Desenvolvimento de Medicamentos , Neoplasias/tratamento farmacológico , Sulfonamidas/uso terapêutico , Fatores Etários , Antineoplásicos/farmacologia , Biomarcadores , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos , Humanos , Recidiva , Projetos de Pesquisa , Sulfonamidas/farmacologia , Resultado do TratamentoRESUMO
Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) model was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co-administration with RTV. The magnitude and time course of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine's plasma exposure by RTV diminishes by approximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV's last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the reduced dose (2.5 mg QD) for 5 days after the last dose of RTV would increase daily average SBP by a maximum of 5.8 mmHg. Based on these results, either approach of resuming amlodipine's full dose could be appropriate when combined with appropriate clinical monitoring.
Assuntos
Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Ritonavir/farmacocinética , Adulto , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ritonavir/uso terapêutico , Distribuição Tecidual/fisiologiaRESUMO
To assess drug-drug interaction (DDI) potential for the three direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir, and paritaprevir, in vitro studies profiled drug-metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, organic anion-transporting polypeptide (OATP) 1B1/1B3, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations, but additional physiologically based pharmacokinetic modeling was necessary to achieve the same for drug transporters. When perpetrator interactions were assessed, ritonavir was responsible for the strong increase in exposure of sensitive CYP3A substrates, whereas paritaprevir (an OATP1B1/1B3 inhibitor) greatly increased the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to moderately increase plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir, and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates) but were not affected by strong CYP3A4 inhibitors, since ritonavir (a CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increased plasma exposure of dasabuvir (a major CYP2C8 substrate), OATP1B1/1B3 inhibitors increased plasma exposure of paritaprevir (an OATP1B1/1B3 substrate), and P-gp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increased plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability may enable better clinical management of nonstudied drug combinations with the 3D regimen.
Assuntos
Anilidas/metabolismo , Antivirais/metabolismo , Carbamatos/metabolismo , Interações Medicamentosas/fisiologia , Compostos Macrocíclicos/metabolismo , Ritonavir/metabolismo , Sulfonamidas/metabolismo , Uracila/análogos & derivados , 2-Naftilamina , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anilidas/farmacologia , Antivirais/farmacologia , Carbamatos/farmacologia , Linhagem Celular , Ciclopropanos , Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Células HEK293 , Hepacivirus/efeitos dos fármacos , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/farmacologia , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Prolina/análogos & derivados , Ritonavir/farmacologia , Sulfonamidas/farmacologia , Uracila/metabolismo , Uracila/farmacologia , ValinaRESUMO
Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro-in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro-in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.
Assuntos
Indutores do Citocromo P-450 CYP2B6/farmacologia , Células Cultivadas , Interações Medicamentosas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , HumanosRESUMO
In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene-related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.
Assuntos
Transtornos de Enxaqueca , Piridinas , Pirróis , Ciência Translacional Biomédica , Humanos , Peptídeo Relacionado com Gene de Calcitonina , Qualidade de Vida , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.
Assuntos
Transtornos de Enxaqueca , Piperidinas , Piridinas , Pirróis , Compostos de Espiro , Ciência Translacional Biomédica , Adulto , Humanos , Peptídeo Relacionado com Gene de Calcitonina , Anticorpos Monoclonais , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.
Assuntos
Combinação de Medicamentos , Estradiol , Hidrocarbonetos Fluorados , Acetato de Noretindrona , Pós-Menopausa , Pré-Menopausa , Pirimidinas , Equivalência Terapêutica , Humanos , Feminino , Estradiol/farmacocinética , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Adulto , Pessoa de Meia-Idade , Acetato de Noretindrona/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Hidrocarbonetos Fluorados/farmacocinética , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/efeitos adversos , Estudos Cross-Over , Cápsulas , Área Sob a Curva , Disponibilidade Biológica , Adulto Jovem , Noretindrona/administração & dosagem , Noretindrona/farmacocinética , Noretindrona/efeitos adversos , Administração Oral , Método Duplo-CegoRESUMO
In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.
Assuntos
Endometriose , Humanos , Feminino , Equivalência Terapêutica , Composição de Medicamentos , ComprimidosRESUMO
Objective: Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS). Design: A phase 2, multicenter, double-blind, randomized, placebo-controlled trial. Setting: Outpatient and academic medical centers. Patients: One hundred fourteen women with PCOS (aged 18-35 years, body mass index 18.5-38 kg/m2). Interventions: Patients were randomized 2:2:2:2:2:3 to elagolix (25 mg twice daily, 50 mg once daily, 75 mg twice daily, 150 mg once daily, and 300 mg twice daily) or placebo. Main Outcome Measures: The primary endpoint was menstrual cycle normalization (defined as 2 menstrual cycles 21-35 days in length during the 4-month treatment period). The secondary endpoint was change from baseline to week 1 in the area under the luteinizing hormone (LH) serum concentration-time curve (AUC). Additional endpoints included change from baseline in serum hormone levels. Results: No significant improvement in restoring normal menstrual cycles was observed in treated subjects; 3 of 114 patients met the primary endpoint. Six patients experienced progesterone elevations indicative of ovulation. The LH levels decreased from baseline to week 16, and LH AUC was significantly reduced from baseline to week 1 in all elagolix treatment groups (P<.1 vs placebo). Follicle-stimulating hormone (FSH) levels generally remained stable through week 16, with no significant differences in FSH AUCs. Serum estradiol and testosterone concentrations were consistently reduced from baseline in all elagolix dose groups compared with placebo. Adverse event rates were similar across treatment groups. Conclusions: Elagolix treatment did not normalize the ovulatory cycle in patients with PCOS. Clinical Trial Registration Number: NCT03951077.
RESUMO
ABBV-47D11 is a neutralizing monoclonal antibody that targets a mutationally conserved hydrophobic pocket distal to the ACE2 binding site of SARS-CoV-2. This first-in-human safety, pharmacokinetics, and antiviral pharmacodynamic assessment in patients with COVID-19 provide an initial evaluation of this antibody that may allow further development. This multicenter, randomized, double-blind, and placebo-controlled single ascending dose study of ABBV-47D11 (180, 600, or 2400 mg) as an intravenous infusion, was in hospitalized and non-hospitalized (confined) adults with mild to moderate COVID-19. Primary outcomes were grade 3 or higher study drug-related adverse events and infusion-related reactions. Secondary outcomes were pharmacokinetic parameters and concentration-time profiles to Day 29, immunogenicity (anti-drug antibodies), and antiviral activity (change in RT-PCR viral load) from baseline to Days 15 and 29. ABBV-47D11 single doses up to 2400 mg were safe and tolerated and no safety signals were identified. The pharmacokinetics of ABBV-47D11 were linear and showed dose-proportional increases in serum concentrations with ascending doses. The exploratory anti-SARS-CoV-2 activity revealed a reduction of viral load at and above the 600 mg dose of ABBV-47D11 regardless of patient demographics and baseline characteristics, however; because of the high inter-individual variability and small sample size a statistical significance was not reached. There is potential for anti-SARS-CoV-2 activity with ABBV-47D11 doses of 600 mg or higher, which could be evaluated in future clinical trials designed and powered to assess viral load reductions and clinical benefit.
Assuntos
COVID-19 , Adulto , Humanos , SARS-CoV-2 , Anticorpos Monoclonais/farmacocinética , Antivirais , Anticorpos NeutralizantesRESUMO
This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice-daily on days 3-11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5-hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix-omeprazole drug-drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice-daily for 9 days increased omeprazole exposure by 1.8-fold and decreased the metabolite-to-parent ratio for 5-hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite-to-parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2- to 2.5-fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5-hydroxyomeprazole decreased by 20%-30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3-fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19-mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Hidrocarbonetos Fluorados , Omeprazol , Pirimidinas , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Interações Medicamentosas , Feminino , Genótipo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Omeprazol/farmacocinética , Omeprazol/farmacologia , Pirimidinas/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids. METHODS: Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach. RESULTS: Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids. CONCLUSIONS: Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).
Assuntos
Hormônio Liberador de Gonadotropina , Leiomioma , Ensaios Clínicos Fase III como Assunto , Estradiol/uso terapêutico , Feminino , Humanos , Hidrocarbonetos Fluorados , Leiomioma/complicações , Leiomioma/tratamento farmacológico , Acetato de Noretindrona , PirimidinasRESUMO
Selection of a personalized dose for an individual patient can be informed by the patient's preferences, translated as weights on each of the clinically relevant safety and efficacy drug attributes, based on results from a brief patient preference elicitation questionnaire. In this analysis, the weighted attributes were simulated to represent various endometriosis patient profiles. Exposure-response simulations were performed for elagolix, a drug approved for management of moderate to severe pain associated with endometriosis, across a range of plasma exposures corresponding to a range of doses. The results were combined to calculate a personalized clinical utility index. An interactive user-friendly online application was developed and envisioned as a physician's desk tool to personalize the dose selection process based on individual patient preferences. This demonstration should serve as an example of how patient/physician conversation can be facilitated with quantitative tools for personalizing the dose.
Assuntos
Analgésicos/administração & dosagem , Endometriose/tratamento farmacológico , Hidrocarbonetos Fluorados/administração & dosagem , Modelos Biológicos , Dor/tratamento farmacológico , Preferência do Paciente , Pirimidinas/administração & dosagem , Adolescente , Adulto , Analgésicos/sangue , Analgésicos/farmacocinética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Endometriose/complicações , Endometriose/metabolismo , Feminino , Humanos , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Pessoa de Meia-Idade , Dor/sangue , Dor/etiologia , Medicina de Precisão , Pirimidinas/sangue , Pirimidinas/farmacocinética , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-dose hormonal add-back therapy can reduce hypoestrogenic effects associated with elagolix, thus there is a need to determine if there is a pharmacokinetic interaction between elagolix and low-dose hormonal add-back therapy. METHODS: Two multiple-dose, open-label, single-sequence, non-randomized studies for elagolix 300 mg twice daily with oral (n = 24) and transdermal (n = 36) low-dose add-back therapy (estradiol [E2]/norethindrone acetate [NETA]; 1 mg/0.5 mg oral and 0.51 mg/4.8 mg transdermal) in healthy postmenopausal women were conducted, with pharmacokinetic sampling for E2, estrone (E1), and NETA up to 72 or 96 h after dosing. Pharmacokinetic parameters for hormones were estimated using noncompartmental methods. RESULTS: No change in norethindrone maximum plasma concentration or area under the concentration-time curve was observed when oral E2/NETA was administered with elagolix. For E2, there was a 2-fold increase in maximum plasma concentration and a 1.5-fold increase in the area under the concentration-time curve, and for E1 there was a 1.7-fold increase in maximum plasma concentration when oral E2/NETA was administered with elagolix. Exposures for norethindrone, E2, and E1 were unchanged when transdermal E2/NETA was applied with elagolix administration. CONCLUSIONS: Although changes in E2/E1 exposures were observed when oral E2/NETA was co-administered with elagolix, these changes are not considered clinically relevant; and no dose adjustments are recommended when elagolix is co-administered with oral or transdermal low-dose add-back therapy.
Assuntos
Estradiol , Hidrocarbonetos Fluorados , Acetato de Noretindrona , Pirimidinas , Interações Medicamentosas , Quimioterapia Combinada , Feminino , HumanosRESUMO
Antibody drug conjugates (ADCs) provide targeted delivery of cytotoxic agents directly inside tumor cells. However, many ADCs targeting solid tumors have exhibited limited clinical efficacy, in part, due to insufficient penetration within tumors. To better understand the relationship between ADC tumor penetration and efficacy, previously applied Krogh cylinder models that explore tumor growth dynamics following ADC administration in preclinical species were expanded to a clinical framework by integrating clinical pharmacokinetics, tumor penetration, and tumor growth inhibition. The objective of this framework is to link ADC tumor penetration and distribution to clinical efficacy. The model was validated by comparing virtual patient population simulations to observed overall response rates from trastuzumab-DM1 treated patients with metastatic breast cancer. To capture clinical outcomes, we expanded upon previous Krogh cylinder models to include the additional mechanism of heterogeneous tumor growth inhibition spatially across the tumor. This expansion mechanistically captures clinical response rates by describing heterogeneous ADC binding and tumor cell killing; high binding and tumor cell death close to capillaries vs. low binding, and high tumor cell proliferation far from capillaries. Sensitivity analyses suggest that clinical efficacy could be optimized through dose fractionation, and that clinical efficacy is primarily dependent on the ADC-target affinity, payload potency, and tumor growth rate. This work offers a mechanistic basis to predict and optimize ADC clinical efficacy for solid tumors, allowing dosing strategy optimization to improve patient outcomes.
Assuntos
Ado-Trastuzumab Emtansina/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/farmacocinética , Modelos Biológicos , Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos/administração & dosagem , Área Sob a Curva , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Imunoconjugados/administração & dosagem , Distribuição Tecidual , Carga TumoralRESUMO
Elagolix is a novel, oral gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose-dependent suppression of estradiol (E2) in clinical studies. A dose-response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen [CTX]), formation (N-terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in -0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Cálcio/metabolismo , Endometriose/tratamento farmacológico , Hidrocarbonetos Fluorados/farmacologia , Farmacologia em Rede/métodos , Pirimidinas/farmacologia , Adolescente , Adulto , Densidade Óssea/fisiologia , Ensaios Clínicos como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Esquema de Medicação , Endometriose/sangue , Endometriose/metabolismo , Estradiol/sangue , Estradiol/metabolismo , Feminino , Humanos , Hidrocarbonetos Fluorados/uso terapêutico , Vértebras Lombares , Modelos Biológicos , Pirimidinas/uso terapêutico , Adulto JovemRESUMO
Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.
Assuntos
Densidade Óssea , Imidazóis , Feminino , Humanos , Lactação , Acetato de Medroxiprogesterona , Gravidez , SulfonasRESUMO
Decline of bone mineral density (BMD) during menopause is related to increased risk of fractures in postmenopausal women, however, this relationship in premenopausal women has not been established. To quantify this relationship, real-world data (RWD) from the National Health and Nutrition Examination Survey (NHANES), and longitudinal data from the elagolix phase III clinical trials were modeled across a wide age range, and covariates were evaluated. The natural changes in femoral neck BMD (FN-BMD) were well-described by a bi-exponential relationship with first-order BMD formation (k1 ) and resorption (k2 ) rate constants. Body mass index (BMI) and race (i.e., Black) were significant predictors indicating that patients with high BMI or Black race experience a relatively lower BMD loss. Simulations suggest that untreated premenopausal women with uterine fibroids (UFs) from elagolix phase III clinical trials (median age 43 years [minimum 25-maximum 53]) lose 0.6% FN-BMD each year up to menopausal age. For clinical relevance, the epidemiological FRAX model was informed by the simulation results to predict the 10-year risk of major osteoporotic fracture (MOF). Premenopausal women with UFs, who received placebo only in the elagolix phase III trials, have a projected FN-BMD of 0.975 g/cm2 at menopause, associated with a 10-year risk of MOF of 2.3%. Integration of modeling, RWD, and clinical trials data provides a quantitative framework for projecting long-term postmenopausal risk of fractures, based on natural history of BMD changes in premenopausal women. This framework enables quantitative evaluation of the future risk of MOF for women receiving medical therapies (i.e., GnRH modulators) that adversely affect BMD.