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The intranasal (IN) route of administration is important for topical drugs and drugs intended to act systemically. More recently, direct nose-to-brain input was considered to bypass the blood-brain barrier.Processes related to IN absorption and nose-to-brain distribution are complex and depend, sometimes in contrasting ways, on chemico-physical and structural parameters of the compounds, and on formulation options.Due to the intricacies of these processes and despite the large number of articles published on many different IN compounds, it appears that absorption after IN dosing is not yet fully understood. In particular, at variance of the understanding and modelling approaches that are available for predicting the pharmacokinetics (PK) following oral administration of xenobiotics, it appears that there is not a similar understanding of the chemico-physical and structural determinants influencing drug absorption and disposition of compounds after IN administration, which represents a missed opportunity for this research field. This is even more true regarding the understanding of the direct nose-to-brain input. Due to this, IN administrations may represent an interesting and open research field for scientists aiming to develop PK property predictions tools, mechanistic PK models describing rate and extent of IN absorption, and translational tools to anticipate the clinical PK following IN dosing based on in vitro and in vivo non clinical experiments.This review intends to provide: i) some basic knowledge related to the physiology of PK after IN dosing, ii) a non-exhaustive list of preclinical and clinical examples related to compounds explored for the potential nose-to-blood and nose-to-brain passage, and iii) the identification of some areas requiring improvements, the understanding of which may facilitate the development of IN drug candidates.
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Administración Intranasal , Humanos , Barrera Hematoencefálica/metabolismo , Animales , Encéfalo/metabolismo , Xenobióticos/farmacocinética , Xenobióticos/administración & dosificación , Farmacocinética , Mucosa Nasal/metabolismoRESUMEN
Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.
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Anticuerpos Monoclonales , Antineoplásicos Inmunológicos , Adolescente , Adulto , Niño , Humanos , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Premature ejaculation (PE) is a common male neurobiological sexual disorder, related to a disturbance in central serotonin (5-hydroxytryptamine or 5-HT) neurotransmission. AIM: To assess the efficacy of a single oral dose of 5HT1A receptor antagonist GSK958108 on ejaculation latency time (ELT) in male subjects suffering from PE. METHODS: A total of 35 male subjects were enrolled in a Phase 1 double-blind, placebo-controlled, parallel group masturbation-model study. All subjects completed the study. No subject was withdrawn from the study. There were no major protocol deviations reported during the study. OUTCOMES: The primary outcome of the study was to evaluate the effect of a single oral dose of 5HT1A receptor antagonist GSK958108 on ELT as measured in the masturbation model; additionally, we investigated drug's safety and tolerability. RESULTS: In the 3 mg GSK958108 treatment group, the ELT was estimated to be 16% longer (1.542 vs 1.328, 95% CI: -16% to +61%) than if the subjects had taken placebo. In the 7 mg GSK958108 treatment group, the ELT was estimated to be 77% longer (2.346 vs 1.328, 95% CI: +28% to +144%) than in the placebo group. The systemic exposure to GSK958108 increased with dosage between 3 mg and 7 mg. A significant trend toward an increase of ELT was observed with increasing plasma concentrations of GSK958108. A total of 4 patients all treated with 7 mg dose experienced minor drug related adverse events (5 adverse events in 4 patients): somnolence (n = 3), headache (n = 1), tinnitus (n = 1). CLINICAL IMPLICATIONS: In the current double-blind, placebo-controlled parallel group study the 5HT1A receptor antagonist GSK958108 was tested in 3 mg and 7 mg doses for PE treatment in humans. It was shown that GSK958108 significantly delayed ejaculation showing a new and safe alternative in PE treatment. STRENGTHS & LIMITATIONS: The present study showed innovative results suggesting an important role of 5HT1A receptor antagonist in the PE treatment. However, the use of masturbation model and the small population are the main limitations of this investigation. CONCLUSION: 5HT1A receptor antagonist GSK958108 3 mg per day and 7 mg per day was found to be well-tolerated, safe and effective for the treatment of PE subjects and demonstrated a strong association between 5HT1A receptors and ejaculation control in humans (NCT00861484). Migliorini F, Tafuri A, Bettica P, et al. A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation. J Sex Med 2021;18:63-71.
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Eyaculación Prematura , Antagonistas del Receptor de Serotonina 5-HT1 , Método Doble Ciego , Eyaculación , Humanos , Masculino , Eyaculación Prematura/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina , Resultado del TratamientoRESUMEN
AIMS: Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor. METHODS: The study had a 2-treatment, 1-sequence, crossover design. Pharmacokinetics (PK) and CYP2C8 genotype were assessed in healthy male subjects administered selexipag (200 µg twice daily [b.i.d.]) alone or with clopidogrel (300 mg single dose or 75 mg once daily [o.d.]). PK modelling and simulation were conducted to support dosing recommendations. RESULTS: Clopidogrel had a comparatively small effect on selexipag (<1.5-fold difference in any PK variable). For ACT-333679, the major contributor to the drug effect, the area under the plasma concentration-time curve during a dose interval and the maximum plasma concentration increased 2.25-fold (90% confidence interval [CI] 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg. The effect of clopidogrel on selexipag and ACT-333679 exposure was comparable for all identified CYP2C8 genotypes. PK simulations predicted comparable exposure to ACT-333679 following selexipag 400 µg b.i.d., 400 µg o.d. in combination with clopidogrel 75 mg o.d and 200 µg b.i.d. with clopidogrel 75 mg o.d. CONCLUSION: Results suggest that ACT-333679 exposure can be maintained within the therapeutic range by reducing selexipag dosing frequency to o.d. or dose to half, when selexipag is coadministered with clopidogrel.
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Acetamidas , Acetamidas/efectos adversos , Clopidogrel/efectos adversos , Citocromo P-450 CYP2C8 , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , PirazinasRESUMEN
This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax: animals, 1 h; humans, 2-3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91-98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2-12%) versus humans (19%). Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals.
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Inhibidores de Proteínas Quinasas/metabolismo , Pirazoles/metabolismo , Quinoxalinas/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Administración Oral , Animales , Área Bajo la Curva , Bilis/metabolismo , Biotransformación , Perros , Heces , Glucurónidos/metabolismo , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Clorhidrato de Bendamustina/farmacocinética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirazoles/metabolismo , Pirimidinas/metabolismo , Rituximab/farmacocinética , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Piperidinas , Resultado del TratamientoRESUMEN
Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.
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Hígado/patología , Trabectedina/efectos adversos , Trabectedina/farmacocinética , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Trabectedina/sangreRESUMEN
The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic-pharmacodynamic (PK-PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor growth inhibition (TGI) models, drug-to-biomarker, e.g. indirect response models, and biomarker-to-tumor, e.g. the more recent biomarker-driven TGI models. In particular, this paper derives a mathematical relationship that guarantees the steady-state equivalence of the cascade of drug-to-biomarker and biomarker-to-tumor models with a drug-to-tumor TGI model. Using the Simeoni TGI model as a reference, conditions for steady-state equivalence are worked out and used to derive a new biomarker-driven model. Simulated and real data are used to show that in realistic cases the steady-state equivalence extends also to transient responses. The possibility of predicting the drug-to-tumor potency of a new candidate drug based only on biomarker response is discussed.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Modelos Biológicos , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral , Simulación por Computador , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND OBJECTIVES: A genetic algorithm (GA) approach was developed to predict drug-drug interactions (DDIs) caused by cytochrome P450 2C8 (CYP2C8) inhibition or cytochrome P450 2B6 (CYP2B6) inhibition or induction. Nighty-eight DDIs, obtained from published in vivo studies in healthy volunteers, have been considered using the area under the plasma drug concentration-time curve (AUC) ratios (i.e., ratios of AUC of the drug substrate administered in combination with a DDI perpetrator to AUC of the drug substrate administered alone) to describe the extent of DDI. METHODS: The following parameters were estimated in this approach: the contribution ratios (CRCYP2B6 and CRCYP2C8, i.e., the fraction of the dose metabolized via CYP2B6 or CYP2C8, respectively) and the inhibitory or inducing potency of the perpetrator drug (IRCYP2B6, IRCYP2C8 and ICCYP2B6, for inhibition of CYP2B6 and CYP2C8, and induction of CYP2B6, respectively). The workflow consisted of three main phases. First, the initial estimates of the parameters were estimated through GA. Then, the model was validated using an external validation. Finally, the parameter values were refined via a Bayesian orthogonal regression using all data. RESULTS: The AUC ratios of 5 substrates, 11 inhibitors and 19 inducers of CYP2B6, and the AUC ratios of 19 substrates and 23 inhibitors of CYP2C8 were successfully predicted by the developed methodology within 50-200% of observed values. CONCLUSIONS: The approach proposed in this work may represent a useful tool for evaluating the suitable doses of a CYP2C8 or CYP2B6 substrates co-administered with perpetrators.
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Algoritmos , Área Bajo la Curva , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C8 , Interacciones Farmacológicas , Interacciones Farmacológicas/fisiología , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/genética , Humanos , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C8/genética , Inhibidores del Citocromo P-450 CYP2C8/farmacología , Inhibidores del Citocromo P-450 CYP2B6/farmacología , Inhibidores del Citocromo P-450 CYP2B6/farmacocinética , Teorema de BayesRESUMEN
Xenograft models are commonly used in oncology drug development. Although there are discussions about their ability to generate meaningful data for the translation from animal to humans, it appears that better data quality and better design of the preclinical experiments, together with appropriate data analysis approaches could make these data more informative for clinical development. An approach based on mathematical modeling is necessary to derive experiment-independent parameters which can be linked with clinically relevant endpoints. Moreover, the inclusion of biomarkers as predictors of efficacy is a key step towards a more general mechanism-based strategy.
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Modelos Biológicos , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
The purpose of this study was to characterize the ponesimod effect on the heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic model developed in healthy participants was updated using data from phase II and III trials conducted in patients with MS. Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re-initiation. The maximal effect parameter of the PK/HR model was lower in patients with MS (23.5% decrease) compared with healthy volunteers (43.2%). The effect of patient covariates on PK/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. After 2 weeks of treatment with 10 mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20 mg, tolerance was maintained > 60% of the steady-state tolerance for up to 4 days after the last dose. Re-initiating with gradual uptitration is recommended if drug discontinuation lasts ≥ 4 days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first 2 weeks of treatment in patients with relapsing MS with a baseline HR > 55 bpm. This justifies the recommendation included in the human prescription drug labeling to monitor HR after the first ponesimod dose in these patients.
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Esclerosis Múltiple , Receptores de Lisoesfingolípidos , Humanos , Frecuencia Cardíaca , Esclerosis Múltiple/tratamiento farmacológico , TiazolesRESUMEN
BACKGROUND: Numerous drugs have the potential to be affected by cytochrome P450 (CYP) 2B6-mediated drug-drug interactions (DDIs). OBJECTIVES: In this work, we extend a static approach to the prediction of the extent of pharmacokinetics DDIs between substrates and inhibitors or inducers of CYP2B6. METHODS: This approach is based on the calculation of two parameters (the contribution ratio [CR], representing the fraction of dose of the substrate metabolized via this pathway and the inhibitory or inducing potency of the perpetrator [IR or IC, respectively]) calculated from the area under the concentration-time curve (AUC) ratios obtained in in-vivo DDI studies. RESULTS: Forty-eight studies involving 5 substrates, 11 inhibitors and 18 inducers of CYP2B6 (overall 15 inhibition and 33 induction studies) were divided into test and validation sets and considered for estimation of the parameters. The proposed approach demonstrated a fair accuracy for predicting the extent of DDI related to CYP2B6 inhibition and induction, all predictions related to the validation test (N = 18) being 50-200% of the observed ratios. CONCLUSIONS: This methodology can be used for proposing initial dose adaptations to be adopted, for example in clinical use or for designing DDI studies involving this enzyme.
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Citocromo P-450 CYP2B6 , Área Bajo la Curva , Interacciones Farmacológicas , HumanosRESUMEN
The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Adulto , Crotonatos , Humanos , Hidroxibutiratos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos , Recurrencia , Tiazoles , Toluidinas , Resultado del TratamientoRESUMEN
A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.
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Neoplasias , Pirazoles , Femenino , Humanos , Neoplasias/tratamiento farmacológico , Fosfatos/uso terapéutico , Pirazoles/farmacocinética , Quinoxalinas/farmacocinéticaRESUMEN
BACKGROUND: Ohno and Colleagues proposed an approach for predicting drug-drug interactions (DDIs) mediated by cytochrome P450 (CYP) 3A4 based on the use of the ratio of the inhibited to non-inhibited area under the plasma concentration time curve (AUC) of substrates to estimate the fraction of the dose metabolized via CYP3A4 (contribution ratio, CR) and the in vivo inhibitory potency of a perpetrator (inhibition ratio, IR). This study evaluated the performance of this approach on DDIs mediated by CYP2C8 inhibitors. RESEARCH DESIGN AND METHODS: Initial estimates of CR and IR of CYP2C8 substrates and inhibitors were calculated for 33 DDI in vivo studies. The approach was externally validated with 17 additional studies. Bayesian orthogonal regression was used to refine the estimates of the parameters. Assessment of prediction success was conducted by plotting observed versus predicted AUC ratios. RESULTS: Final estimates of CRs and IRs were obtained for 19 CYP2C8 substrates and 23 inhibitors, respectively. The method demonstrated good predictive capacity, with only two values outside of the prespecified limits. CONCLUSIONS: The approach may help to adapt dose regimens for CYP2C8 substrates when given in combination with CYP2C8 inhibitors and to map the potential DDIs of new molecular entities.
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Inhibidores del Citocromo P-450 CYP2C8 , Interacciones Farmacológicas , Teorema de Bayes , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Humanos , Preparaciones FarmacéuticasRESUMEN
Introduction:Safety and tolerability is a critical area where improvements are needed to decrease the attrition rates during development of new drug candidates. Modeling approaches, when smartly implemented, can contribute to this aim.Areas covered:The focus of this review was on modeling approaches applied to four kinds of drug-induced toxicities: hematological, immunological, cardiovascular (CV) and liver toxicity. Papers, mainly published in the last 10 years, reporting models in three main methodological categories - computational models (e.g., quantitative structure-property relationships, machine learning approaches, neural networks, etc.), pharmacokinetic-pharmacodynamic (PK-PD) models, and quantitative system pharmacology (QSP) models - have been considered.Expert opinion:The picture observed in the four examined toxicity areas appears heterogeneous. Computational models are typically used in all areas as screening tools in the early stages of development for hematological, cardiovascular and liver toxicity, with accuracies in the range of 70-90%. A limited number of computational models, based on the analysis of drug protein sequence, was instead proposed for immunotoxicity. In the later stages of development, toxicities are quantitatively predicted with reasonably good accuracy using either semi-mechanistic PK-PD models (hematological and cardiovascular toxicity), or fully exploited QSP models (immuno-toxicity and liver toxicity).
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Modelos Biológicos , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Hígado , Aprendizaje AutomáticoRESUMEN
BACKGROUND: Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day. OBJECTIVE: The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension. METHODS: Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2-600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters. RESULTS: The final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters. CONCLUSIONS: The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.
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Hipertensión Arterial Pulmonar , Adulto , Femenino , Voluntarios Sanos , Humanos , Pirimidinas , SulfonamidasRESUMEN
OBJECTIVE: The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. METHODS: Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. RESULTS: In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52 L/h) and a moderate mean apparent volume of distribution at steady state (239 L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9 ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20 mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within one week. CONCLUSIONS: The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.
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Esclerosis Múltiple , Humanos , Recuento de Linfocitos , Linfocitos , Esclerosis Múltiple/tratamiento farmacológico , TiazolesRESUMEN
BACKGROUND AND OBJECTIVE: Ponesimod is a sphingosphine-1-phosphate receptor modulator being developed for the treatment of multiple sclerosis. The effects of disease-modifying treatments on magnetic resonance imaging (MRI) lesions in relapsing multiple sclerosis accurately predict effects on clinical relapses, therefore MRI lesion counts are generally accepted efficacy endpoints in phase II clinical studies of multiple sclerosis disease-modifying treatments. Here, we characterize the effect of ponesimod systemic exposure on the cumulative number of T1 gadolinium-enhancing (Gd+) lesions and the annualized relapse rate in a phase IIb study. METHODS: This study assessed the cumulative number of new Gd+ lesions on T1-weighted MRI scans (primary endpoint) at weeks 12, 16, 20, and 24 and the annualized relapse rate (secondary endpoint). The effect of the demographic and prognostic covariates of sex, age, weight, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were explored. Analyses were performed using NONMEM, Version 7.3.0 (ICON plc). RESULTS: An increase in ponesimod exposure led to a statistically significant decrease in the cumulative T1 Gd+ lesions on MRI from week 12 to 24 of treatment. Increasing the ponesimod daily dose beyond 20 mg did not provide significant additional benefits. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were associated with a higher number of new cumulative T1 Gd+ from week 12 to 24 of treatment. CONCLUSIONS: This analysis shows a relationship between ponesimod exposure and the cumulative number of new T1 Gd+ lesions. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Score at baseline were not found to be importantly associated with the magnitude of ponesimod effect, and consequently, there is no indication from these analyses that dosage adjustments based on the explored covariates are warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01006265, registration date 1 November, 2009.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Lactante , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Tiazoles , Resultado del TratamientoRESUMEN
Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.