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1.
Br J Clin Pharmacol ; 90(2): 504-515, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37864281

RESUMO

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.


Assuntos
Hipertensão , Lisinopril , Adulto , Humanos , Adolescente , Criança , Lactente , Pré-Escolar , Lisinopril/efeitos adversos , Projetos Piloto , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Rim , Peso Corporal
2.
Drug Metab Dispos ; 51(4): 499-508, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36639242

RESUMO

Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.


Assuntos
Modelos Biológicos , Monobactamas , Adulto , Humanos , Ceftazidima , Antibacterianos , Músculos
3.
J Pharmacokinet Pharmacodyn ; 50(2): 133-144, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36648595

RESUMO

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently. This study aims to demonstrate that the latent variable IDR approach provides a convenient longitudinal exposure-response modeling framework to assess potential interaction effects of combination therapies. This is illustrated by an application to the exposure-response modeling of guselkumab, a monoclonal antibody in clinical development that blocks the interleukin-23p19 subunit, and golimumab, a monoclonal antibody that binds with high affinity to tumor necrosis factor-alpha. A Phase 2a study was conducted in 214 patients with moderate-to severe active ulcerative colitis for which longitudinal assessments of disease severity based on patient-reported measures of rectal bleeding, stool frequency, and symptomatic remission were evaluated as categorical endpoints, and fecal calprotectin as a continuous endpoint. The modeling results suggested independent pharmacodynamic guselkumab and golimumab effects on fecal calprotectin as a continuous endpoint, as well as interaction effects on the categorical endpoints that may be explained by an additional pathway of competitive interaction.


Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Resultado do Tratamento , Índice de Gravidade de Doença
4.
Artigo em Inglês | MEDLINE | ID: mdl-37952005

RESUMO

Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions.

5.
J Pharmacol Exp Ther ; 383(1): 70-79, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36041884

RESUMO

JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.v. or 1, 3 and 10 mg/kg s.c. Plasma and liver concentrations were analyzed simultaneously using nonlinear mixed-effects modeling with the NONMEM 7.4. A population PK model consisting of a two-compartment disposition model with transporter-mediated drug disposition, including internalization to the liver compartment, linear elimination from plasma and liver, and first-order absorption following subcutaneous administration, was suitable to describe both plasma and liver PK. After subcutaneous dosing, absolute bioavailability was complete and flip-flop kinetics were observed. JNJ-73763989 distributes from plasma to liver via transporter-mediated liver internalization in less than 24 hours, with sustained (>42 days) liver exposure. The saturation of transporter-mediated liver internalization was hypothesized to be due to asialoglycoprotein receptor saturation. Increasing the dose decreased the relative liver uptake efficiency in mice for intravenously and, to a lesser extent, subcutaneously administered JNJ-73763989. Lower dose levels administered subcutaneously in mice can maximize the proportion of the dose reaching the liver. SIGNIFICANCE STATEMENT: Pharmacokinetic modeling of JNJ-73763989 liver and plasma concentration-time data in mice indicated that the proportion of JNJ-73763989 reaching the liver may be increased by administering lower subcutaneous doses compared to higher intravenous doses. Model-based simulations can be applied to optimize the dose and regimen combination.


Assuntos
Hepatite B Crônica , Acetilgalactosamina , Animais , Receptor de Asialoglicoproteína , Dependovirus/genética , Vírus da Hepatite B , Masculino , Camundongos , RNA Mensageiro , RNA Interferente Pequeno
6.
Br J Clin Pharmacol ; 88(10): 4481-4493, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35470450

RESUMO

AIMS: Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin 23, is approved for the treatment of plaque psoriasis (PsO) and psoriatic arthritis (PsA), palmoplantar pustulosis (PPP), generalized pustular psoriasis, and erythrodermic psoriasis in various countries. The purpose of this analysis was to develop a comprehensive population pharmacokinetic (PK) model for guselkumab to determine whether PK differs across different disease populations and healthy subjects. METHODS: A nonlinear mixed-effects modelling approach was used to analyse 23 097 serum PK samples obtained from 2623 healthy subjects and patients with PsO, PsA and PPP across 9 phase 1-3 clinical trials. RESULTS: Guselkumab concentrations were adequately described by a 2-compartment linear PK model with first-order absorption and elimination. Clearance (CL), central and peripheral volume of distribution, intercompartmental flow, absorption rate constant and absolute bioavailability estimates were 0.255 L/d, 3.60 L, 1.78 L, 0.369 L/d, 0.313 d-1 and 49.2%, respectively, for a subject weighing 70 kg. Terminal half-life was estimated to be approximately 14.6 days. Body weight was the primary factor affecting CL and central volume of distribution. CL of guselkumab was similar among patients with PsA, PsO and PPP, but CL in disease populations was 11-17% lower than that in healthy subjects after other covariate effects such as body weight were considered. CONCLUSION: The population pharmacokinetic analysis indicated that, after other covariate effects were taken into account, patients with PsO, PsA and PPP had similar PK characteristics, with CL in these disease populations being slightly lower than in healthy individuals.


Assuntos
Artrite Psoriásica , Exantema , Psoríase , Doença Aguda , Anticorpos Monoclonais Humanizados , Artrite Psoriásica/tratamento farmacológico , Peso Corporal , Doença Crônica , Voluntários Saudáveis , Humanos , Psoríase/tratamento farmacológico , Psoríase/metabolismo
7.
Br J Clin Pharmacol ; 88(12): 4985-4996, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36256514

RESUMO

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.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Adolescente , Adulto , Criança , Humanos , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Projetos de Pesquisa
8.
Mol Pharm ; 18(3): 952-965, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33400546

RESUMO

Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (i.e., intramuscular and subcutaneous) administration were correlated with the in vitro intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the in vivo performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform in vitro measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain in vivo representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain in vitro measurements to predict the in vivo PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (i.e., maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.


Assuntos
Diarilquinolinas/química , Diarilquinolinas/farmacocinética , Suspensões/química , Suspensões/farmacocinética , Água/química , Animais , Química Farmacêutica/métodos , Excipientes/química , Excipientes/farmacocinética , Masculino , Poloxâmero/química , Poloxâmero/farmacocinética , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química , Tensoativos/farmacocinética , Termodinâmica , Vitamina E/química , Vitamina E/farmacocinética
9.
Br J Clin Pharmacol ; 87(3): 1203-1214, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32693432

RESUMO

AIMS: Lisinopril is an angiotensin converting enzyme inhibitor to treat hypertension. It shows complex pharmacokinetics (PK), and its PK behaviour in paediatric populations is not well characterized. The aim of this study was to develop a physiologically based PK (PBPK) model for lisinopril to describe the drug's PK in children. METHODS: The PBPK model development was performed in a step-wise manner. An adult model was initially developed to characterize lisinopril's disposition and absorption and verified using literature data. Subsequently, the adult PBPK model was extrapolated to the paediatric population (0.5-18 years old) by accounting for age-dependent physiological and anatomical changes. Model performance was evaluated by comparing the PK profiles and drug exposures of observed vs predicted data. RESULTS: The disposition of lisinopril was well described by a minimal PBPK model-an effective strategy to capture the biphasic elimination of the drug. The absorption of lisinopril was described by the intestinal peptide transporter-mediated uptake. The adult model adequately described the literature data with predictions within a twofold range of clinical observations. Good model predictivity was also observed in children older than 6 years of age. The model overpredicted the drug exposure in children under 6 years, probably due to not incorporating the actual, unknown ontogeny of the intestinal peptide transporter. CONCLUSIONS: The PBPK model predicted the PK of lisinopril in adults and children above 6 years of age well. Model refinement in children under 6 years warrants future informative ontogeny data of the intestinal peptide transporter.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Lisinopril , Adolescente , Adulto , Criança , Pré-Escolar , Previsões , Humanos , Lactente , Modelos Biológicos
10.
Food Microbiol ; 88: 103407, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31997763

RESUMO

Most interesting antifungal compounds from sourdough fermentation are acetic acid (AA) and DL-3-phenyllactic acid (PLA). Although the role of pH on the activity of organic acids has been established long time ago, no information is available on the importance of undissociated acid (HA) expressed on the aqueous phase of bread (CHA, mmole/L). Mostly, concentrations (mmole/kg dough or bread, CTOT) and pH are given side by side. The aim of this study was to show the importance of CHA for adequate comparison of in-vitro growth data with bread shelf-life. Growth of Penicillium paneum and Aspergillus niger was recorded using a micro-dilution assay with optical density measurements. Parameters such as aw (0.94-0.98), pH (4.6-6.0), temperature (10-30 °C), time (0-8 days) and CTOT (0-300 mM) were varied. Growth/no-growth models were developed and shelf-life tests of par-baked breads of 45 days at 20 °C were conducted. The modelled inhibitory concentrations of undissociated acid were comparable with the shelf-life test of bread: (PLA) 50 versus 39-84 mmol/L; (AA) 110 versus 110-169 mmol/L. This study showed the applicability of G/NG models for bread shelf-life prediction and highlighted the importance of CHA. Moreover, it was found that naturally present PLA in sourdough bread is insufficient to increase bread shelf-life.


Assuntos
Ácido Acético/farmacologia , Antifúngicos/farmacologia , Pão/microbiologia , Conservantes de Alimentos/farmacologia , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Lactatos/farmacologia , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/crescimento & desenvolvimento , Meios de Cultura/química , Microbiologia de Alimentos/métodos , Conservação de Alimentos/métodos , Armazenamento de Alimentos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Modelos Biológicos , Penicillium/efeitos dos fármacos , Penicillium/crescimento & desenvolvimento
11.
Food Microbiol ; 88: 103406, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31997762

RESUMO

This study aims to assess, by means of a full factorial design, the effect of storage temperature (10-30 °C), water activity (aw, 0.87-0.89), headspace oxygen (O2) level (0.15-0.80%) and pasteurization intensity (95 °C-105 °C/15sec) on the time to visible growth (tv, days) of Aspergillus fischerianus on acidified Potato Dextrose Agar (aPDA, pH 3.6) for up to 90 days. Moreover, in order to validate the results obtained on aPDA, 12 conditions were selected and assessed in concentrate strawberry-puree based medium. Overall, storage temperature had the greatest effect on the tv of A. fischerianus on the evaluated conditions. At 10 °C, no visible growth was observed over the 90 day incubation period, whilst visible mycelia (diameter ≥ 2 mm) were present in 37% and 89% of the conditions at 22 °C and 30 °C, respectively. Pasteurization intensity had only a minor effect on the outgrowth of A. fischerianus. Growth inhibition was observed when aw was reduced to 0.870 ± 0.005 in combination with very low headspace O2 levels (0.15% ± 0.10) in both, aPDA and concentrate strawberry-based media, regardless of the incubation temperature and heat pasteurization intensity. Overall, longer tv's were required when incubation was done at 22 °C compared to 30 °C. Ultimately, the effect of O2 (0.05 and 1%) and pasteurization intensity (95 °C and 105 °C/15sec) were evaluated on totally 22 fruit purees (un-concentrates and concentrates) over a 60 day storage period. None of the concentrates purees (aw ≤0.860) evaluated in this study supported the growth of A. fischerianus. On the other hand, A. fischerianus growth inhibition was only observed when the O2 levels were ≤0.05% on un-concentrates fruit purees (aw ≥ 0.980) stored at ambient temperature (22 °C). Combination of multiple stress factors effectively inhibited growth of A. fischerianus. In general, storage of fruit purees at low temperatures (<10 °C) or distribution in the form of concentrates can be considered as important strategies to prevent the growth of spoilage associated heat-resistant moulds.


Assuntos
Aspergillus/crescimento & desenvolvimento , Conservação de Alimentos/métodos , Temperatura Alta , Oxigênio/metabolismo , Pasteurização , Água , Aspergillus/metabolismo , Contagem de Colônia Microbiana , Manipulação de Alimentos/métodos , Microbiologia de Alimentos/métodos , Armazenamento de Alimentos/métodos , Fragaria/microbiologia , Frutas/microbiologia , Concentração de Íons de Hidrogênio , Neosartorya/crescimento & desenvolvimento , Esporos Fúngicos/crescimento & desenvolvimento
13.
Br J Clin Pharmacol ; 85(5): 1003-1014, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30761579

RESUMO

AIMS: Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects. METHODS: Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics. RESULTS: A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold. CONCLUSIONS: A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.


Assuntos
Acetamidas/farmacocinética , Antidepressivos/farmacocinética , Modelos Biológicos , Acetamidas/administração & dosagem , Administração Oral , Antidepressivos/administração & dosagem , Área Sob a Curva , Povo Asiático , Variação Biológica da População , Estudos Cross-Over , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Voluntários Saudáveis , Humanos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Taxa de Depuração Metabólica , Comprimidos , Equivalência Terapêutica , Adulto Jovem
14.
Pharm Res ; 36(9): 127, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236836

RESUMO

PURPOSE: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. METHODS: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. RESULTS: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. CONCLUSIONS: The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.


Assuntos
Paclitaxel Ligado a Albumina/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Peritoneais/tratamento farmacológico , Paclitaxel Ligado a Albumina/química , Paclitaxel Ligado a Albumina/farmacocinética , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Portadores de Fármacos , Gelatina/química , Humanos , Iridoides/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Microesferas , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Food Microbiol ; 83: 9-17, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31202423

RESUMO

The aims of this study were (i) screening of antifungal activity of thyme essential oil on Penicillium paneum; (ii) development of growth/no-growth models (G/NG); and (iii) validation of the G/NG models by performing bread baking trials. The screening method was based on the measurement of fungal growth in a semi-solid medium through optical density. The combined influence of aw (0.88-0.97), pH (4.8-7.0), temperature (22 and 30 °C), time (0-144 h) and varying concentrations of thyme oil (0-2 µL/mL YES) were assessed. Growth of P. paneum at aw 0.88 was significantly reduced compared to aw 0.93-0.97. A slight pH effect was observed at aw 0.93; growth was delayed at pH 6 compared to pH 4.8. The lowest concentration of thyme oil preventing growth during 144 h of incubation was 1 µL/mL medium. According to the results of the shelf-life test of par-baked bread, fungal growth was inhibited for more than 45 days using 0.3 mL thyme oil/100 g dough. To conclude, this study recognized the potential of using G/NG models to develop better product formulations and to facilitate product innovation.


Assuntos
Antifúngicos/farmacologia , Óleos Voláteis/farmacologia , Penicillium/efeitos dos fármacos , Penicillium/crescimento & desenvolvimento , Temperatura , Thymus (Planta)/química , Pão/microbiologia , Microbiologia de Alimentos , Conservação de Alimentos/métodos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Água
16.
Artigo em Inglês | MEDLINE | ID: mdl-29987142

RESUMO

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or per os (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% did for Pseudomonas aeruginosa and 3% for Staphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ciprofloxacina/farmacocinética , Ciprofloxacina/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Enterobacteriaceae/efeitos dos fármacos , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Infecções Urinárias/microbiologia
17.
Eur J Clin Pharmacol ; 74(5): 593-599, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29392351

RESUMO

BACKGROUND: Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. AIMS: The aim of this study was to develop "reference ranges" for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. METHODS: Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. RESULTS: Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7-41.6 ng/mL 0-4 h post dose and 10.6-37.1 ng/mL 20-24 h post dose. These ranges increased to 221-624 ng/mL 0-4 h post dose following administration of a 30-mg dose, and 159-557 ng/mL 20-24 h post dose. The 80% reference range 0-4 h post dose was 22.5-67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179-768 ng/mL following a 150-mg dose once daily of oral quetiapine. CONCLUSIONS: Comparing individual patients' APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.


Assuntos
Antipsicóticos/sangue , Aripiprazol/sangue , Benzodiazepinas/sangue , Modelos Biológicos , Fumarato de Quetiapina/sangue , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/farmacocinética , Aripiprazol/farmacocinética , Benzodiazepinas/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Fumarato de Quetiapina/farmacocinética , Valores de Referência , Adulto Jovem
18.
Eur J Clin Pharmacol ; 74(3): 297-305, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29198064

RESUMO

PURPOSE: For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, "children are not small adults," and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication. METHODS: Population pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis. RESULTS: The half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-µg lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-µg tablet, even when the same exposure is achieved. CONCLUSIONS: A new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation.


Assuntos
Antidiuréticos/administração & dosagem , Desamino Arginina Vasopressina/administração & dosagem , Composição de Medicamentos , Modelos Biológicos , Enurese Noturna/tratamento farmacológico , Administração Sublingual , Adolescente , Fatores Etários , Antidiuréticos/sangue , Antidiuréticos/farmacocinética , Antidiuréticos/uso terapêutico , Criança , Estudos Cross-Over , Desamino Arginina Vasopressina/sangue , Desamino Arginina Vasopressina/farmacocinética , Desamino Arginina Vasopressina/uso terapêutico , Feminino , Liofilização , Humanos , Capacidade de Concentração Renal/efeitos dos fármacos , Masculino , Avaliação das Necessidades , Enurese Noturna/sangue , Enurese Noturna/urina , Concentração Osmolar , Projetos Piloto , Comprimidos , Urinálise
19.
J Pharmacokinet Pharmacodyn ; 45(6): 765-785, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30298439

RESUMO

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp®. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration-time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration-time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.


Assuntos
Modelos Biológicos , Uso Off-Label , Propofol/farmacologia , Adulto , Fatores Etários , Criança , Ensaios Enzimáticos/métodos , Feminino , Humanos , Recém-Nascido , Rim/citologia , Rim/metabolismo , Fígado/citologia , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Recombinantes/metabolismo
20.
Pharm Res ; 34(2): 333-351, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27864744

RESUMO

PURPOSE: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. METHODS: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. RESULTS: A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%). CONCLUSIONS: A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.


Assuntos
Acetaminofen/farmacocinética , Encéfalo/metabolismo , Morfina/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Humanos , Masculino , Modelos Biológicos , Modelos Teóricos , Ratos , Ratos Wistar , Distribuição Tecidual/fisiologia
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