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1.
Toxicol Sci ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32421801

RESUMO

p-Cresol is a uremic toxin that is formed by intestinal microbiota and extensively conjugated by first-pass metabolism. p-Cresol glucuronide exerts various forms of cellular toxicity in vitro and is accumulated in the plasma of subjects with kidney disease, where associations with adverse cardiovascular and renal outcomes are evident. The objective of this study was to determine the contributions of human UDP-glucuronosyltransferase (UGT) enzymes in the formation of p-cresol glucuronide. Utilizing commonly expressed hepatic or renal human recombinant UGTs (i.e. hrUGT-1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17), hrUGT1A6 and hrUGT1A9 exhibited the highest catalytic activities in the generation of p-cresol glucuronide. The kinetics of p-cresol glucuronide formation in hrUGT1A6 and pooled human liver microsomes were best described by the Hill equation and in hrUGT1A9 and pooled human kidney microsomes by substrate inhibition. Using inhibitory and selective UGT inhibitors (i.e. acetaminophen or amentoflavone for UGT1A6 and niflumic acid for UGT1A9), UGT1A6 was identified the predominant enzyme responsible for p-cresol glucuronide production in pooled human liver (78.4-81.3% contribution) and kidney (54.3-62.9%) microsomes, whereas UGT1A9 provided minor contributions (2.8% and 35.5%, respectively). The relative contributions of UGT1A6 (72.6±11.3%, mean±SD) and UGT1A9 (5.7±4.1%) in individual human liver microsomes from 12 adult donors were highly variable, where an inverse association (R=-0.784, p = 0.003) between UGT1A6 contribution and UGT1A9 probe substrate activity (i.e. mycophenolic acid) was evident. Our novel findings provide valuable tools for conducting further mechanistic studies and for designing clinical interventions to mitigate the toxicities associated with p-cresol glucuronide.

2.
Toxicol Sci ; 173(2): 267-279, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742356

RESUMO

Mycophenolic acid (MPA) is commonly prescribed for preventing graft rejection after kidney transplantation. The primary metabolic pathways of MPA are hepatic glucuronidation through UDP-glucuronosyltransferase (UGT) enzymes in the formation of MPA-glucuronide (MPAG, major pathway) and MPA-acyl glucuronide (AcMPAG). p-Cresol, a potent uremic toxin known to accumulate in patients with renal dysfunction, can potentially interact with MPA via the inhibition of glucuronidation. We hypothesized that the interaction between MPA and p-cresol is clinically relevant and that the estimated exposure changes in the clinic are of toxicological significance. Using in vitro approaches (ie, human liver microsomes and recombinant enzymes), the potency and mechanisms of inhibition by p-cresol towards MPA glucuronidation were characterized. Inter-individual variabilities, effects of clinical co-variates, in vitro-in vivo prediction of likely changes in MPA exposure, and comparison to other toxins were determined for clinical relevance. p-Cresol inhibited MPAG formation in a potent and competitive manner (Ki=5.2 µM in pooled human liver microsomes) and the interaction was primarily mediated by UGT1A9. This interaction was estimated to increase plasma MPA exposure in patients by approximately 1.8-fold, which may result in MPA toxicity. The mechanism of inhibition for AcMPAG formation was noncompetitive (Ki=127.5 µM) and less likely to be clinically significant. p-Cresol was the most potent inhibitor of MPA-glucuronidation compared with other commonly studied uremic toxins (eg, indole-3-acetic acid, indoxyl sulfate, hippuric acid, kynurenic acid, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) and its metabolites (ie, p-cresol sulfate and p-cresol glucuronide). Our findings indicate that the interaction between p-cresol and MPA is of toxicological significance and warrants clinical investigation.

3.
Clin Pharmacokinet ; 58(12): 1533-1552, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31332670

RESUMO

Mycophenolic acid is commonly prescribed in adult kidney transplant recipients for preventing graft rejection. A therapeutic target for total mycophenolic acid area under the concentration-time curve (30-60 mg h/L) has been established in adult kidney transplant recipients and widely referenced today. However, this specific target range does not adequately characterize mycophenolic acid-associated adverse effects. The primary objective of this qualitative and critical review was to characterize the exposure-toxicity relationships of mycophenolic acid in an attempt to determine whether exposure thresholds can be identified. The secondary objective was to determine the associations of clinical variables with specific adverse effects. The inclusion criteria consisted of all peer-reviewed papers in adult kidney transplant subjects (average study age > 18 years) with both exposure (area under the concentration-time curve) and toxicity data. The exclusion criteria were papers involving the pediatric population, studies lacking either area under the concentration-time curve or toxicity data, or studies with no apparent reported variations in area under the concentration-time curves. Of the 28 papers identified, inconsistent findings have been reported for the most frequently characterized adverse events of mycophenolic acid (gastrointestinal, infectious, and hematological), while promising exposure thresholds (i.e., > 40-60 mg h/L for total mycophenolic acid) have been suggested by a few studies. The roles of free mycophenolic acid exposure, mycophenolic acid metabolites, or clinical factors influencing the manifestation of the toxicities also remain to be clarified. Although it is not yet possible to define toxicity threshold(s) for the purpose of mycophenolic acid therapeutic drug monitoring, the information obtained and the limitations identified in this comprehensive literature body have provided a good foundation for future investigations.

4.
Clin Pharmacokinet ; 58(11): 1483-1495, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31055791

RESUMO

BACKGROUND AND OBJECTIVE: Mycophenolic acid is commonly prescribed to adult kidney transplant recipients. Mycophenolic acid is extensively metabolized to mycophenolic acid-glucuronide (major metabolite) and mycophenolic acid-acyl-glucuronide (minor metabolite). We hypothesized that (1) adult kidney transplant patients on corticosteroid-free regimens exhibit unique mycophenolic acid population pharmacokinetics compared with patients receiving corticosteroid-based therapy, and (2) mycophenolic acid clearance is directly dependent on glucuronide metabolite formation. METHODS: Non-linear mixed-effects modeling was conducted with MonolixSuite-2018R1 (n = 27). Optimal pharmacokinetic models were selected based on objective function values, standard errors, and biological plausibility. RESULTS: Clinical demographic data were sex (female, 16), age (47 ± 13 years, mean ± standard deviation), weight (70 ± 16 kg), height (165 ± 9 cm), albumin (43 ± 4 g/L), serum creatinine (102 ± 27 µmol/L), estimated glomerular filtration rate (61 ± 16 mL/min/1.73 m2), mycophenolic acid dosage (1.4 ± 0.5 g/day, as mycophenolate mofetil), and tacrolimus dosage (5 ± 3 mg/day, immediate release). The population pharmacokinetics of mycophenolic acid can be described by a two-compartment first-order absorption with lag time, and a linear elimination structural model. The apparent oral clearance estimate in the final model (population mean, relative standard error) was 2.87 L/h, 42.3%, which is lower than that reported for similar patients on corticosteroid-based regimens (11.9-26.3 L/h). Other pharmacokinetic parameters were comparable to historical data obtained in corticosteroid-based patients. Both mycophenolic acid-acyl-glucuronide trough concentration and the area under the concentration-time curve ratio were significant covariates that reduced mycophenolic acid apparent oral clearance from 16.5 (base model) to 2.87 L/h. The model was evaluated based on bootstrapping, visual predictive checks, and diagnostic plots. CONCLUSIONS: Our novel findings suggest the potential need to reduce mycophenolic acid dosage in subjects on corticosteroid-free regimens. Corticosteroid-free subjects may also be more sensitive to drug/gene interactions.

5.
Biomed Chromatogr ; 33(8): e4549, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30958902

RESUMO

Mycophenolic acid (MPA), a frequently used immunosuppressant, exhibits large inter-patient pharmacokinetic variability. This study (a) developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for MPA and metabolites [MPA glucuronide (MPAG) and acyl-glucuronide (AcMPAG)] in the culture medium of HepaRG cells; and (b) characterized the metabolism interaction between MPA and p-cresol (a common uremic toxin) in this in vitro model as a potential mechanism of pharmacokinetic variability. Chromatographic separation was achieved with a C18 column (4.6 × 250 mm,5 µm) using a gradient elution with water and methanol (with 0.1% formic acid and 2 mm ammonium acetate). A dual ion source ionization mode with positive multiple reaction monitoring was utilized. Multiple reaction monitoring mass transitions (m/z) were: MPA (320.95 → 207.05), MPAG (514.10 → 303.20) and AcMPAG (514.10 → 207.05). MPA-d3 (323.95 → 210.15) and MPAG-d3 (517.00 → 306.10) were utilized as internal standards. The calibration curves were linear from 0.00467 to 3.2 µg/mL for MPA/MPAG and from 0.00467 to 0.1 µg/mL for AcMPAG. The assay was validated based on industry standards. p-Cresol inhibited MPA glucuronidation (IC50 ≈ 55 µm) and increased MPA concentration (up to >2-fold) at physiologically relevant substrate-inhibitor concentrations (n = 3). Our findings suggested that fluctuations in p-cresol concentrations might be in part responsible for the large pharmacokinetic variability observed for MPA in the clinic.


Assuntos
Cromatografia Líquida/métodos , Cresóis/metabolismo , Ácido Micofenólico/metabolismo , Espectrometria de Massas em Tandem/métodos , Linhagem Celular , Cresóis/análise , Cresóis/farmacocinética , Interações Medicamentosas , Humanos , Limite de Detecção , Modelos Lineares , Ácido Micofenólico/análise , Ácido Micofenólico/farmacocinética , Reprodutibilidade dos Testes
6.
Eur J Drug Metab Pharmacokinet ; 44(6): 729-741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31006833

RESUMO

Therapeutic drug monitoring (TDM) of tacrolimus in whole blood obtained from venipuncture is routinely practiced. Dried blood spotting (DBS) may act as a suitable alternative for tacrolimus TDM due to relative ease of sampling and processing. The objective of this literature review was to provide a critical evaluation on the feasibility (i.e., accuracy and precision) of DBS for predicting tacrolimus whole blood concentrations in solid organ transplant recipients. A comprehensive systematic literature search using PubMed, Scopus, EMBASE, and Google Scholar was conducted. The primary objective was to extract the bias and precision data from the identified papers. In addition, the collection, storage, and analysis protocols were also summarized. Both adult and pediatric data were included. The reported bias data (primarily based on individual concentrations) in the majority of studies were within acceptable limits (< 15%). However, the precision data were not consistently reported. The area under the concentration-time curve of tacrolimus derived from DBS appeared to be a better predictor of whole blood compared to single concentrations based on a limited number of studies. No apparent differences in prediction were observed between pediatric and adult patients. Small sample sizes and the lack of complete description of the study population were common limitations. DBS is a promising approach for tacrolimus TDM. However, in order for DBS to become a useful substitute for tacrolimus whole blood monitoring in solid organ transplant patients, further systematic studies with sufficient power and comprehensive prediction error analyses are required.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Tacrolimo/sangue , Adulto , Humanos , Imunossupressores/sangue , Masculino , Transplante de Órgãos , Flebotomia , Transplantados
7.
Eur J Drug Metab Pharmacokinet ; 44(3): 409-422, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30377942

RESUMO

BACKGROUND AND OBJECTIVE: Tacrolimus is the mainstay calcineurin inhibitor frequently administered with mycophenolic acid with or without corticosteroids to prevent graft rejection in adult kidney transplant recipients. The primary objective of this study was to develop and evaluate a population pharmacokinetic model characterizing immediate-release oral tacrolimus co-administered with mycophenolate mofetil (a pro-drug of mycophenolic acid) in adult kidney transplant recipients on corticosteroid-free regimens. The secondary objective was to investigate the effects of clinical covariates on the pharmacokinetics of tacrolimus, emphasizing the interacting effects of mycophenolic acid. METHODS: Population modeling and evaluation were conducted with Monolix (Suite-2018R1) using the stochastic approximation expectation-maximization algorithm in 49 adult subjects (a total of 320 tacrolimus whole-blood concentrations). Effects of clinical variables on tacrolimus pharmacokinetics were determined by population covariate modeling, regression modeling, and categorical analyses. RESULTS: A two-compartment, first-order absorption with a lag-time, linear elimination, and constant error model best represented the population pharmacokinetics of tacrolimus. The apparent clearance value for tacrolimus was 17.9 l/h (6.95% relative standard error) in our model, which is lower compared with similar subjects on corticosteroid-based therapy. The glomerular filtration rate had significant effects on the apparent clearance and central compartment volume of distribution. Conversely, mycophenolic acid did not affect the apparent clearance of tacrolimus. CONCLUSION: We have developed and internally evaluated a novel population pharmacokinetic model for tacrolimus co-administered with mycophenolate mofetil in corticosteroid-free adult kidney transplant patients. These findings are clinically important and provide further reasons for conducting therapeutic drug monitoring in this specific population.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Modelos Biológicos , Ácido Micofenólico/farmacocinética , Tacrolimo/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Liberação Controlada de Fármacos , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/sangue , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/sangue
8.
Eur J Drug Metab Pharmacokinet ; 44(4): 437-458, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30535757

RESUMO

Several HepaRG three-dimensional (3D) in vitro model systems have been developed to improve the predictability of xenobiotic metabolism and toxicity. In this review, we present a detailed summary and critique of the performance of various HepaRG 3D models compared to the conventional 2D monolayer culture. HepaRG 3D models can be broadly categorized into (1) scaffold-free, (2) scaffold-based, and (3) bioartificial liver (BAL) models. With respect to the scaffold-free configurations, the hanging drop model closely mimics the normal physiological function and metabolic profile of the liver. The micromold model is suitable for high-throughput multiplexed assays and exhibits higher accuracy when predicting drug-induced liver toxicity risk in both acute and chronic culture. Scaffold- and BAL-based models also present improved precision and accuracy for hepatotoxic drug screening in addition to allowing improved model control to closely mimic physiological assay conditions. Overall, all 3D HepaRG models exhibit improved cellular function, metabolic activity, and toxicity screening ability compared to the conventional 2D monolayer culture. These improvements reported in 3D models may be due to a higher degree of differentiation and cell polarity. Nevertheless, the expression and functions of various phase II, phase III, and nuclear receptors need to be further characterized in these 3D models.


Assuntos
Técnicas de Cultura de Células/métodos , Fígado/efeitos dos fármacos , Xenobióticos/efeitos adversos , Xenobióticos/metabolismo , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Fígado Artificial
9.
Clin Drug Investig ; 38(11): 1011-1022, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30178220

RESUMO

BACKGROUND AND OBJECTIVES: The hematological side effects associated with mycophenolic acid (MPA) are relatively common and have severe consequences. The majority of literature data have not shown clear consistency in the MPA exposure-neutropenia relationship. We hypothesized that (i) adult de novo kidney transplant recipients who develop neutropenia have relatively higher dose-normalized MPA exposure than patients without neutropenia, and (ii) the observed neutropenia may be explained by polymorphisms in metabolism and/or transporter genes responsible for MPA disposition. METHODS: Adult kidney transplant recipients on steady-state tacrolimus and MPA, not receiving a corticosteroid, and with stable renal function were recruited for investigation at three periods post-transplant (1, 3, and 12 months; n = 21, 17, and 13, respectively). Clinical variables (age, weight, MPA daily dose, albumin, serum creatinine, absolute neutrophil count), tacrolimus and MPA concentrations (for exposure calculation), and genotypes (UGT2B7 G211T, UGT2B7 C802T, UGT1A9 T-275A, UGT1A9 T98C, MRP2 C-24T, MRP2 G1249A, OATP1B1 A388G, OATP1B1 C463A) were characterized. RESULTS: A significant inverse association between dose-normalized MPA exposure (a surrogate marker for apparent MPA clearance) and absolute neutrophil count in all three study periods (r2 ~ 0.3-0.7) was observed. No associations between characterized single nucleotide polymorphisms and MPA exposure or absolute neutrophil count were established. However, significant alterations in the minor allele frequencies of UGT2B7*2 C802T, UGT1A9 T275A, and MRP2 G1249A were evident. CONCLUSION: These findings support the clinical strategy for conducting MPA therapeutic drug monitoring in adult kidney transplant patients on steroid-free immunosuppressant therapy. The novel population genomic analysis data warrant further epidemiological investigations in a larger study sample.


Assuntos
Genômica/métodos , Transplante de Rim , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/sangue , Neutrófilos/efeitos dos fármacos , Transplantados , Adulto , Idoso , Contagem de Células/métodos , Feminino , Frequência do Gene/genética , Humanos , Transplante de Rim/tendências , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Esteroides
11.
Eur J Drug Metab Pharmacokinet ; 43(5): 509-531, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29557529

RESUMO

Elbasvir and grazoprevir, in a fixed-dose combination of 50 and 100 mg, respectively, have received approval to be administered orally once daily, with or without ribavirin, for the treatment of chronic hepatitis C virus (HCV) infections. The absorption characteristics of elbasvir and grazoprevir have been adequately summarized, although differences were observed for grazoprevir (e.g., increased exposure at steady state in patients), but not elbasvir, between healthy and HCV-infected subjects. Inconsistencies with respect to absorption were also reported on the effects of food or acid reducers (famotidine or pantoprazole) in the literature. Many distribution characteristics of elbasvir and grazoprevir have been obtained from in vitro models, using incubation conditions that were in many cases inconsistent with normal physiological conditions in humans. Elbasvir and grazoprevir appear to undergo modest hepatic metabolism and are excreted primarily unchanged (~ 80% parent drug found) in feces. Both elbasvir and grazoprevir are substrates of cytochrome P450 (CYP) 3A4 enzyme, but mechanistic experiments were lacking to demonstrate the role of other enzymes and the precise relative % contribution of CYP3A4. The pharmacokinetics of elbasvir and grazoprevir have been characterized in various special populations (elderly, male vs. female, Caucasian vs. Asian, renal impairment, and hepatic impairment). Other than moderate and severe hepatic impairment where administrations are contraindicated, no dose adjustments are required for both drugs in these special patient populations. The available drug-drug interaction data provided some consistency between in vitro and in vivo observations and, in some instances, can provide predictions of likely clinically relevant scenarios.


Assuntos
Antivirais/farmacocinética , Benzofuranos/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , Biotransformação , Citocromo P-450 CYP3A/metabolismo , Combinação de Medicamentos , Interações Medicamentosas , Fezes/química , Feminino , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Medição de Risco , Fatores de Risco , Adulto Jovem
12.
Am J Health Syst Pharm ; 75(6): 351-358, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29367424

RESUMO

PURPOSE: Results of a study comparing testosterone exposure and tolerability with subcutaneous versus i.m. administration are presented. METHODS: In a prospective, open-label, crossover study, adult participants already on stable i.m. testosterone gender-affirming therapy self-injected testosterone cypionate or enanthate i.m. for 3 weeks followed by subcutaneous injections for 8 weeks. Trough serum testosterone concentrations were determined weekly, and serial total serum testosterone (TST) concentrations were determined on postinjection days 1, 3, and 5 of weeks 3 and 11. Hemoglobin and alanine transaminase (ALT) levels were measured at week 3 (the first visit), with repeat measurements at week 11 (the final visit). The dose-normalized area under the time-concentration curve (AUC) was calculated during weeks 3 and 11. RESULTS: Fourteen transgender males (mean age, 30 ± 10 years) participated in the study. The mean hemoglobin values at the first and final visits were 160 ± 9 and 153 ± 9 g/L, respectively (p > 0.05); the mean ALT values were 18 ± 6 and 21 ± 10 IU/L (p > 0.05). Total testosterone exposure was comparable with subcutaneous versus i.m. injection (mean AUC, 1.7 ± 0.6 nmol·days/L/mg versus 1.9 ± 0.6 nmol·days/L/mg; p > 0.05). Information collected via weekly questionnaires indicated that the subcutaneous route was more tolerable, with lower self-reported scores for preinjection anxiety, pain during injection, and postinjection pain. CONCLUSION: The subcutaneous route for the injection of testosterone was well tolerated and appeared to be as effective as i.m. injection in delivering equivalent TST levels, although there was wide intrapatient and interpatient variability.


Assuntos
Tolerância a Medicamentos , Injeções Intramusculares , Injeções Subcutâneas , Segurança do Paciente , Testosterona/administração & dosagem , Testosterona/farmacocinética , Adulto , Estudos Cross-Over , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Pessoas Transgênero , Adulto Jovem
13.
Clin Pharmacokinet ; 57(5): 547-558, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28861847

RESUMO

The most recent comprehensive reviews on the population pharmacokinetics of mycophenolic acid (MPA) were published in 2014. Since then, several population pharmacokinetic studies on MPA have been published. The majority of literature is still focused on the kidney transplant population, although studies have also been conducted in liver and lung transplantation, autoimmune diseases, and hematopoietic stem cell transplant. While the majority of the model building is still based on parametric non-linear mixed-effects modeling, recent studies suggest the suitability of other methodologies. Additionally, instead of just focusing on pharmacokinetic modeling, a trend toward describing the relationships between pharmacokinetic and pharmacodynamic parameters is observed. Given the importance of enterohepatic recirculation (EHR) in the pharmacokinetics of MPA, more authors have attempted to characterize this process in their models. Overall, the recent models have become more sophisticated and incorporate EHR, pharmacodynamic relationships, and metabolites while maintaining many of the population values and covariates identified previously. However, the number of MPA population pharmacokinetic models describing the enteric-coated formulation of MPA (EC-MPA) is still limited. Given the increasing use of EC-MPA, more studies are needed to fill this literature gap. In addition, few studies are yet available characterizing free MPA concentration or MPA metabolites. Given the extensive protein binding, low to intermediate extraction, and intrinsic clearance characteristics of MPA in humans, including these variables would improve the population structural models.


Assuntos
Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Doenças Autoimunes/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Órgãos
14.
Pharmaceutics ; 9(4)2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29019915

RESUMO

While therapeutic drug monitoring (TDM) that uses blood as the biological matrix is the traditional gold standard, this practice may be impossible, impractical, or unethical for some patient populations (e.g., elderly, pediatric, anemic) and those with fragile veins. In the context of finding an alternative biological matrix for TDM, this manuscript will provide a qualitative review on: (1) the principles of TDM; (2) alternative matrices for TDM; (3) current evidence supporting the use of interstitial fluid (ISF) for TDM in clinical models; (4) the use of microneedle technologies, which is potentially minimally invasive and pain-free, for the collection of ISF; and (5) future directions. The current state of knowledge on the use of ISF for TDM in humans is still limited. A thorough literature review indicates that only a few drug classes have been investigated (i.e., anti-infectives, anticonvulsants, and miscellaneous other agents). Studies have successfully demonstrated techniques for ISF extraction from the skin but have failed to demonstrate commercial feasibility of ISF extraction followed by analysis of its content outside the ISF-collecting microneedle device. In contrast, microneedle-integrated biosensors built to extract ISF and perform the biomolecule analysis on-device, with a key feature of not needing to transfer ISF to a separate instrument, have yielded promising results that need to be validated in pre-clinical and clinical studies. The most promising applications for microneedle-integrated biosensors is continuous monitoring of biomolecules from the skin's ISF. Conducting TDM using ISF is at the stage where its clinical utility should be investigated. Based on the advancements described in the current review, the immediate future direction for this area of research is to establish the suitability of using ISF for TDM in human models for drugs that have been found suitable in pre-clinical experiments.

15.
Can J Hosp Pharm ; 70(3): 171-178, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680170

RESUMO

BACKGROUND: Coadministration of lorazepam and valproic acid is identified by tertiary references as causing a major drug interaction that requires therapy modification and dosage adjustments. The proposed mechanism involves inhibition of lorazepam glucuronidation via direct inhibition of uridine 5'-diphosphate-glucuronosyltransferase enzymes by valproic acid. However, the clinical significance of this interaction is unclear. OBJECTIVES: To identify site-specific practices and assess clinical responses to the interaction between valproic acid and lorazepam. METHODS: A chart review was conducted for patients over 18 years of age who were admitted, from September 2008 to September 2014 inclusive, to the psychiatry or neurology service at Vancouver General Hospital, Vancouver, British Columbia, and who received concomitant valproic acid and lorazepam therapy. RESULTS: Of the 30 patients included in the chart review, 12 (40%) received an intervention. A total of 8 (27%) patients experienced an adverse drug reaction (ADR), such as drowsiness and dizziness. Seven of these 8 patients were among those who received an intervention. The mean dosage (± standard deviation) of lorazepam was 4.2 ± 1.2 mg per day among patients who experienced an ADR and less than 2 mg per day among those who did not experience an ADR. CONCLUSIONS: The current recommendation from tertiary drug references is to reduce the dose of lorazepam by 50% when this drug is coadministered with valproic acid. However, this recommendation could not be validated through an analysis of patients exposed to this interaction in the clinical setting or through a review of the literature. Further clinical and pharmacokinetic studies are required to determine whether concurrent treatment with lorazepam and valproic acid should be considered as causing a major drug interaction. Until more data are available, clinicians should remain cognizant of the potential for a drug-drug interaction and should use the lowest effective dose of lorazepam when this drug is administered concomitantly with valproic acid.

16.
Can J Hosp Pharm ; 69(4): 269-79, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27621486

RESUMO

BACKGROUND: The Winter-Tozer equation for estimating free phenytoin concentration is biased and imprecise. Alternative predictive equations are available, but most remain unvalidated. OBJECTIVES: To assess the bias and precision of the Winter-Tozer equation and selected derivative equations in predicting free phenytoin concentration and to derive new equations with better predictive performance. METHODS: A retrospective chart review (for patients with samples drawn for free phenytoin concentration between September 2008 and September 2013) was conducted for 3 subpopulations (critical care, general medicine, neurology) in one hospital. Patients were included if older than 18 years with values for free phenytoin concentration available and were excluded if phenytoin was not at steady state or if they were undergoing hemodialysis or receiving enzyme inhibitors or inducers that would affect phenytoin clearance. The predictive performance measures used were mean prediction error (MPE), root mean square error, and Bland-Altman plots. Spearman rank correlation and multiple linear regression were performed with log-transformed data. RESULTS: In total, 133 patients were included (70 men [53%]; mean age ± standard deviation 64 ± 19 years; serum creatinine 90.4 ± 64.0 µmol/L; albumin 26.4 ± 7.0 g/L). In the combined population, the Winter-Tozer equation (MPE 1.7 µmol/L, 95% confidence interval [CI] 1.5 to 1.9) and the Anderson equation (MPE 0.5 µmol/L, 95% CI 0.3 to 0.7) over-predicted free phenytoin concentration, whereas the first Kane equation tended to underpredict free phenytoin (MPE -0.2 µmol/L, 95% CI -0.4 to 0.0), and the second Kane equation significantly underpredicted free phenytoin (MPE -0.3 µmol/L, 95% CI -0.5 to -0.1). In each subpopulation, the Winter-Tozer equation overpredicted true concentration with greater bias and imprecision. All equations performed poorly in the critical care subpopulation. Only albumin (R (2) = 0.09) and total phenytoin concentration (R (2) = 0.53) were correlated with free phenytoin concentration. The equation derived by multiple linear regression exhibited significantly less bias and imprecision than the Winter-Tozer equation in the validation set (p < 0.05). A new, user-friendly equation, specific to the authors' patient population, was derived, which had an albumin coefficient of 0.275. CONCLUSIONS: Relatively poor predictive performance of the Winter-Tozer and derivative equations calls for more precise and less biased equations. The novel equations presented here, which had better predictive performance for free phenytoin concentration and were based on a large sample of adult patients, should be further validated in other institutions.

17.
Expert Rev Clin Pharmacol ; 9(12): 1597-1609, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27644147

RESUMO

INTRODUCTION: Similar to other nations North American people used herbs for thousands of years to treat diseases and purify their spirits. By the middle of the 1900s, evidence-based conventional medicine received wide acceptance in Canada and the United States (US). Nowadays, people are going back to their roots and actively using herbal medicines (HMs) and natural health products (NHPs). Areas covered: This article is focusing on use and regulation of the HMs and NHPs in Canada and the US, raises concerns regarding HM and NHP safety and efficacy, offers suggestions on how to overcome these problems. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Use of HMs, especially dietary supplements is widespread among adults in Canada and US. HMs and NHPs are regulated in both countries, but minimum criteria for product approval and post-market surveillance have been set. Concerns of quality, contamination, adulteration, and efficacy in are of central importance in the discussion of HMs and NHPs. Detailed product description and research are of vital importance to ensure safety and efficacy of these products. Additionally, 'herbal' education of healthcare providers and patients is needed to guarantee further successful integration of HM and conventional medicines.


Assuntos
Legislação de Medicamentos , Fitoterapia , Preparações de Plantas/uso terapêutico , Plantas Medicinais , Canadá , Humanos , Estados Unidos
18.
Expert Opin Drug Metab Toxicol ; 12(5): 545-53, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27021063

RESUMO

INTRODUCTION: Mycophenolate (MPA) therapeutic drug monitoring (TDM) in adult solid organ transplant recipients was summarized extensively in consensus reports published between 2009 and 2011. Thus, this review provides an update on the science of MPA TDM over the past 5 years. AREAS COVERED: PubMed and Google Scholar (January 2010-January 2016) were searched; relevant articles from bibliographies of identified articles were extracted for further review. New evidence on TDM-guided dosing in MPA efficacy and toxicity and best approaches for estimating MPA area-under-the-curve for TDM were retrieved. EXPERT OPINION: Since 2011, little advancement in consensus on MPA TDM has been established for any type of solid organ transplant. Lack of systematic studies validating or further defining MPA's target range suggests that routine TDM is still unwarranted. Accurate, precise, and user-friendly limited sampling strategies (LSSs) are available in specific patient populations taking mycophenolate mofetil but not enteric-coated mycophenolate sodium. In absence of outcome data, routine use of LSSs in MPA TDM still cannot be recommended. Further research should attempt to define factors that modulate MPA's pharmacokinetics to elucidate their impact on utility of TDM. Future studies should also validate LSSs in larger patient populations and demonstrate benefits of LSSs in improving patient outcomes.


Assuntos
Monitoramento de Medicamentos/métodos , Imunossupressores/administração & dosagem , Ácido Micofenólico/administração & dosagem , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Transplante de Órgãos/métodos
19.
Ann Pharmacother ; 50(4): 311-25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26825643

RESUMO

OBJECTIVE: In settings where free phenytoin concentrations are not available, the Sheiner-Tozer equation-Corrected total phenytoin concentration = Observed total phenytoin concentration/[(0.2 × Albumin) + 0.1]; phenytoin in µg/mL, albumin in g/dL-and its derivative equations are commonly used to correct for altered phenytoin binding to albumin. The objective of this article was to provide a comprehensive and updated review on the predictive performance of these equations in various patient populations. DATA SOURCES: A literature search of PubMed, EMBASE, and Google Scholar was conducted using combinations of the following terms: Sheiner-Tozer, Winter-Tozer, phenytoin, predictive equation, precision, bias, free fraction. STUDY SELECTION AND DATA EXTRACTION: All English-language articles up to November 2015 (excluding abstracts) were evaluated. DATA SYNTHESIS: This review shows the Sheiner-Tozer equation to be biased and imprecise in various critical care, head trauma, and general neurology patient populations. Factors contributing to bias and imprecision include the following: albumin concentration, free phenytoin assay temperature, experimental conditions (eg, timing of concentration sampling, steady-state dosing conditions), renal function, age, concomitant medications, and patient type. Although derivative equations using varying albumin coefficients have improved accuracy (without much improvement in precision) in intensive care and elderly patients, these equations still require further validation. CONCLUSIONS: Further experiments are also needed to yield derivative equations with good predictive performance in all populations as well as to validate the equations' impact on actual patient efficacy and toxicity outcomes. More complex, multivariate predictive equations may be required to capture all variables that can potentially affect phenytoin pharmacokinetics and clinical therapeutic outcomes.


Assuntos
Albuminas/metabolismo , Fenitoína/farmacocinética , Humanos , Temperatura
20.
Clin Pharmacokinet ; 55(3): 313-58, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26346776

RESUMO

We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva (and vice versa). Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics. Additional confirmatory data are required for drugs (especially in patients) that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters (e.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution. Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further.


Assuntos
Antibacterianos/farmacocinética , Saliva/metabolismo , Aminoglicosídeos/farmacocinética , Monitoramento de Medicamentos , Fluoroquinolonas/farmacocinética , Humanos , Macrolídeos/farmacocinética , Penicilinas/farmacocinética , Tetraciclinas/farmacocinética
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