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BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.
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Imunossupressores , Doenças Inflamatórias Intestinais , Metiltransferases , Tioguanina , Adulto , Azatioprina , Feminino , Genótipo , Nucleotídeos de Guanina , Humanos , Imunossupressores/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Masculino , Mercaptopurina , Metiltransferases/genética , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Tioguanina/farmacocinética , TionucleotídeosRESUMO
BACKGROUND AND AIM: Thiopurines have a favorable benefit-risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6-thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6-methylmercaptopurine (6-MMP). In this case series, we provide a detailed overview of 6-MMP-induced myelotoxicity in inflammatory bowel disease patients. METHODS: We retrospectively scrutinized pharmacological laboratory databases of five participating centers over a 5-year period. Patients with leukocytopenia at time of elevated 6-MMP levels (>5700 pmol/8 × 108 red blood cells) were included for detailed chart review. RESULTS: In this case series, we describe demographic, clinical, and pharmacological aspects of 24 cases of 6-MMP-induced myelotoxicity on weight-based thiopurine therapy with a median steady-state 6-MMP level of 14 500 pmol/8 × 108 red blood cells (range 6600-48 000). All patients developed leukocytopenia (white blood cell count 2.7 ± 0.9 × 109 /L) after a median period of 11 weeks after initiation of thiopurine therapy (interquartile range 6-46 weeks). Eighteen patients (75%) developed concurrent anemia (median hemoglobin concentration 6.9 × 109 /L), and four patients developed concurrent thrombocytopenia (median platelet count 104 × 109 /L). Leukocytopenia resolved in 20 patients (83%) within 4 weeks upon altered thiopurine treatment regimen, and white blood cell count was increasing, but not yet normalized, in the remaining four patients. CONCLUSION: We observed that thiopurine-induced myelotoxicity also occurs because of (extremely) high 6-MMP concentrations in patients with a skewed thiopurine metabolism. Continued treatment with adapted thiopurine therapy was successful in almost all patients.
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Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucopenia/induzido quimicamente , Mercaptopurina/análogos & derivados , Adulto , Hipersensibilidade a Drogas/sangue , Humanos , Leucopenia/sangue , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/sangue , Mercaptopurina/uso terapêutico , Pessoa de Meia-Idade , Erros Inatos do Metabolismo da Purina-Pirimidina/sangue , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND & AIMS: More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD. METHODS: In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]). RESULTS: Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85). CONCLUSIONS: Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.
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Anti-Inflamatórios/administração & dosagem , Azatioprina/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Variação Genética , Leucopenia/prevenção & controle , Mercaptopurina/administração & dosagem , Metiltransferases/genética , Trombocitopenia/prevenção & controle , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/metabolismo , Azatioprina/efeitos adversos , Azatioprina/metabolismo , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Doença de Crohn/diagnóstico , Doença de Crohn/enzimologia , Doença de Crohn/genética , Cálculos da Dosagem de Medicamento , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/metabolismo , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Leucopenia/induzido quimicamente , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Países Baixos , Farmacogenética , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. RESULTS: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. CONCLUSIONS: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.
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Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/uso terapêutico , Mitotano/farmacocinética , Mitotano/uso terapêutico , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , Modelos Estatísticos , Medicina de Precisão , Estudos Retrospectivos , Adulto JovemRESUMO
Background: Exposure-response studies have shown that higher infliximab concentrations are associated with better outcomes in inflammatory bowel disease. There is little agreement about the optimal time to measure infliximab levels in children. Objectives: We aimed to evaluate whether trough levels at week 6 or week 14 predict sustained remission. The secondary aim was to define target trough levels at weeks 6 and 14. Design: We used routinely collected electronic healthcare data of 70 anti-tumour necrosis factor naïve children with inflammatory bowel disease treated with a standard infliximab induction- and variable maintenance scheme. Methods: Trough levels and blood and faecal markers for disease activity were measured before every infliximab administration. Sustained remission was defined as the absence of symptoms and low inflammatory markers between weeks 26 and 52 after the start of infliximab therapy. Optimal infliximab levels at weeks 6 and 14 were determined using the receiver operating characteristic curve. Results: The median infliximab level at week 6 was not significantly higher in children who achieved sustained remission compared to those who did not (16.9 mg/L versus 12.0 mg/L; p = 0.058) but the median infliximab level at week 14 was significantly higher in those with sustained remission (7.7 mg/L versus 3.8 mg/L; p = 0.006). The area under the receiver operating characteristics curves at weeks 6 and 14 to predict sustained remission was 0.67 (95% CI 0.51-0.83) and 0.75 (95% CI 0.60-0.90), respectively. Target trough levels at weeks 6 and 14 were ⩾13.2 and ⩾6.9 mg/L, respectively. Conclusion: An infliximab measurement at week 14 with a target through level ⩾6.9 mg/L best predicted sustained remission.
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BACKGROUND AND OBJECTIVE: Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual's infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. METHODS: In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. RESULTS: The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: -20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. CONCLUSIONS: In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.
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Monitoramento de Medicamentos , Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Infliximab , Modelos Biológicos , Humanos , Infliximab/farmacocinética , Infliximab/administração & dosagem , Infliximab/sangue , Infliximab/uso terapêutico , Criança , Adolescente , Feminino , Masculino , Estudos Retrospectivos , Países Baixos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/sangue , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Monitoramento de Medicamentos/métodos , Estudos de Coortes , Pré-EscolarRESUMO
Background: Inflammatory bowel disease (IBD) is a chronic relapsing-remitting disease. An adverse immune reaction toward the intestinal microbiota is involved in the pathophysiology and microbial perturbations are associated with IBD in general and with flares specifically. Although medical drugs are the cornerstone of current treatment, responses vary widely between patients and drugs. The intestinal microbiota can metabolize medical drugs, which may influence IBD drug (non-)response and side effects. Conversely, several drugs can impact the intestinal microbiota and thereby host effects. This review provides a comprehensive overview of current evidence on bidirectional interactions between the microbiota and relevant IBD drugs (pharmacomicrobiomics). Methods: Electronic literature searches were conducted in PubMed, Web of Science and Cochrane databases to identify relevant publications. Studies reporting on microbiota composition and/or drug metabolism were included. Results: The intestinal microbiota can both enzymatically activate IBD pro-drugs (e.g., in case of thiopurines), but also inactivate certain drugs (e.g., mesalazine by acetylation via N-acetyltransferase 1 and infliximab via IgG-degrading enzymes). Aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors, anti-tumor necrosis factor biologicals and tofacitinib were all reported to alter the intestinal microbiota composition, including changes in microbial diversity and/or relative abundances of various microbial taxa. Conclusion: Various lines of evidence have shown the ability of the intestinal microbiota to interfere with IBD drugs and vice versa. These interactions can influence treatment response, but well-designed clinical studies and combined in vivo and ex vivo models are needed to achieve consistent findings and evaluate clinical relevance.
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Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016-2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.
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Therapeutic drug monitoring (TDM) of tumor necrosis factor-α (TNFα)-inhibitors adalimumab and infliximab is important to establish optimal drug dose and maximize treatment efficacy. Currently, TDM is primarily performed with ELISA techniques in clinical laboratories, resulting in a long sample-to-result workflow. Point-of-care (POC) detection of these therapeutic antibodies could significantly decrease turnaround times and allow for user-friendly home-testing. Here, we adapted the recently developed bioluminescent dRAPPID (dimeric Ratiometric Plug-and-Play Immunodiagnostics) sensor platform to allow POC TDM of infliximab and adalimumab. We applied the two best performing dRAPPID sensors, with limit-of-detections of 1 pM and 17 pM, to measure the infliximab and adalimumab levels in 49 and 40 patient serum samples, respectively. The analytical performance of dRAPPID was benchmarked with commercial ELISAs and yielded Pearson's correlation coefficients of 0.93 and 0.94 for infliximab and adalimumab, respectively. Furthermore, a dedicated bioluminescence reader was fabricated and used as a readout device for the TDM dRAPPID sensors. Subsequently, infliximab and adalimumab patient serum samples were measured with the TDM dRAPPID sensors and bioluminescence reader, yielding Pearson's correlation coefficients of 0.97 and 0.86 for infliximab and adalimumab, respectively, and small proportional differences with ELISA (slope was 0.97 ± 0.09 and 0.96 ± 0.20, respectively). The adalimumab and infliximab dRAPPID sensors, in combination with the dedicated bioluminescence reader, allow for ease-of-use TDM with a fast turnaround time and show potential for POC TDM outside of clinical laboratories.
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BACKGROUND AND OBJECTIVE: Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy. METHODS: Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE). RESULTS: Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies. CONCLUSION: This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase. CLINICAL TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).
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Artrite Reumatoide , Doenças Inflamatórias Intestinais , Humanos , Adalimumab/uso terapêutico , Inibidores do Fator de Necrose Tumoral , Projetos Piloto , Estudos Prospectivos , Teorema de Bayes , Doenças Inflamatórias Intestinais/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológicoRESUMO
There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure-response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.
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BACKGROUND: Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. METHODS: A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. RESULTS: A total of 114 patients (male 39%, Crohn's disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. CONCLUSIONS: At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.
After 12 months, first-line thioguanine therapy was still used by 86% of thiopurine-naïve patients with inflammatory bowel disease and clinically effective in 53%. The safety profile was acceptable and only 8% of patients ceased therapy due to adverse events.
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BACKGROUND: Gentamicin-polymethylmethacrylate (PMMA) beads release gentamicin gradually, and high concentrations develop only locally. It is unclear how frequent and in which patients gentamicin serum concentrations are measurable and possibly lead to toxicity. The aim of this study was to investigate the measurability of gentamicin serum concentrations after the implantation of gentamicin-PMMA beads and to assess the nephrotoxicity of these beads. METHODS: In this observational cohort study, gentamicin and creatinine concentrations were measured in 34 serum samples of 23 patients with implanted gentamicin-PMMA beads for infected hip joints with our regular immunoassay (lower limit of quantitation 0.4 mg/L). Samples were also analyzed with an adjusted immunoassay with a lower limit of quantitation of 0.05 mg/L. RESULTS: Gentamicin serum concentrations were >0.4 mg/L in 9 of 34 (26%) of all the samples measured (both after the first implantation and change of beads) and in 5 of 23 patients (22%) after the first implantation of gentamicin-PMMA beads. Gentamicin serum concentrations were >0.05 mg/L in 31 samples (91%). Nephrotoxicity (defined as increase in serum creatinine >44 µmole/L and/or a relative increase >25%) occurred more frequently in patients with measurable gentamicin serum concentrations than in those without measurable gentamicin serum levels (57% versus 43%, P = 0.02). Both nephrotoxicity and gentamicin serum concentration could not be associated with the number of implanted gentamicin-PMMA beads. CONCLUSIONS: Gentamicin serum concentrations >0.4 mg/L can be measured after the implantation of gentamicin-PMMA beads in certain patients with infected hip joints. Furthermore, elevated (>0.4 mg/L) gentamicin serum concentrations are associated with nephrotoxicity in patients with gentamicin-PMMA beads for infected hip joints.
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Infecções Bacterianas/tratamento farmacológico , Gentamicinas/administração & dosagem , Gentamicinas/uso terapêutico , Articulação do Quadril/patologia , Artropatias/tratamento farmacológico , Metilmetacrilatos/administração & dosagem , Metilmetacrilatos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Estudos de Coortes , Implantes de Medicamento , Gentamicinas/sangue , Humanos , Pessoa de Meia-IdadeRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: From case reports it has become clear that selective serotonin reuptake inhibitors (SSRIs) can cause bleeding disorders. The causative mechanism is as yet unknown. Several publications have described the relationship between the serotonin transporter genotype and the prevalence of certain diseases such as depression, but few have focused on the relationship with side-effects of antidepressive drugs such as SSRIs. WHAT THIS STUDY ADDS: This study suggests that the association between SSRI therapy and prolonged bleeding time may not be related to the polymorphism of the serotonin transporter (5-HTTLPR) investigated. AIMS: Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are associated with an increased risk of bleeding disorders, probably due to decreased platelet serotonin levels. Polymorphisms in the serotonin transporter gene (5-HTT) may influence the risk of SSRI-induced bleedings. The aim of this study was to investigate whether and to what extent the serotonin transporter polymorphism increases the bleeding time in paroxetine users. METHODS: A prospective study, using routinely collected hospital and pharmacy data, was conducted among 43 patients between 18 and 70 years old and on >4 weeks of paroxetine therapy. The genotype for the serotonin transporter (5-HTTLPR), trough paroxetine levels, platelet function analyser (PFA)-closure time (collagen/epinephrine) and a complete blood count were assessed. RESULTS: No significant difference was seen between the SS, SL, LL genotypes of the serotonin transporter and the PFA-closure time. None of the covariates had a significant influence on the association between the serotonin transporter polymorphism and the PFA-closure time. Age and von Willebrand factor showed the largest contribution, but not significant. No difference was seen between the PFA-closure time and the frequency of bruising and spontaneous bleedings between patients with at least one S allele and with the LL genotype. CONCLUSION: Our prospective study does not support the assumption that paroxetine can cause a prolonged PFA-closure time during paroxetine therapy due to a serotonin transporter polymorphism. Old age, use of platelet inhibitors and a history of gastrointestinal bleeding remain the focus for SSRI-induced bleeding complications.
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Plaquetas/metabolismo , Transtorno Depressivo/tratamento farmacológico , Paroxetina/metabolismo , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Idoso , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/uso terapêutico , Estudos ProspectivosRESUMO
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Corticosteroides/efeitos adversos , Corticosteroides/farmacocinética , Corticosteroides/farmacologia , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Monitoramento de Medicamentos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Medicina de PrecisãoRESUMO
BACKGROUND: Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups. RESULTS: A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups. CONCLUSION: Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adesão à Medicação/psicologia , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Adulto , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Imunossupressores/metabolismo , Masculino , Mercaptopurina/metabolismo , Pessoa de Meia-Idade , Inquéritos e Questionários , Tioinosina/análogos & derivados , Tioinosina/sangue , Tionucleotídeos/sangue , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: This study was designed to evaluate whether standardizing total parenteral nutrition (TPN) is at least non-inferior to TPN with individualized composition in premature infants with a gestational age (GA) < 32 weeks. METHODS: In this retrospective cohort study, all preterm born in or transferred to Maxima Medical Center (MMC) within 24 hours after birth with a GA < 32 weeks were included. The individualized group (2011) was compared to the partially standardized group (2012) and completely standardized group (2014) consequently. The primary endpoint was difference in growth. Secondary endpoints included differences in electrolyte concentrations. RESULTS: A total of 299 preterm were included in this study. When comparing weight gain, the infants in the (partially) standardized group demonstrated significantly (P < 0.05) less weight loss during the first days of life and grew faster subsequently in the following days than the individualized TPN regimen. Furthermore, significant differences in abnormal serum sodium, chloride, calcium, creatinine, magnesium and triglycerides values were demonstrated. CONCLUSION: TPN with a (partially) standardized composition revealed to be at least non-inferior to TPN with an individualized composition.
RESUMO
INTRODUCTION: The effective, but expensive, drug infliximab is used in patients with inflammatory bowel disease (IBD). Monitoring infliximab trough levels and anti-infliximab antibody (ATI) formation can lead to a more cost-effective use of infliximab therapy. The aim of our study was to investigate the effect of implementation of a treatment algorithm for infliximab in a single-centre IBD cohort, focussing on remission rates and drug costs. METHODS: IBD patients aged 18 years or older treated with infliximab were asked to participate in this study. Remission rates were assessed using faecal calprotectin levels and a validated questionnaire. Infliximab trough levels and ATIs were determined at baseline and at the third infliximab infusion. According to the advice given by the treatment algorithm, infliximab dosage adjustments were performed at the second infliximab infusion. RESULTS: Between January and December 2015 a total of 62 IBD patients in our centre were treated with infliximab, of whom 33 (53%) patients agreed to participate in this study. The number of patients in remission was 28 (85%) at baseline and there were 13 dose adaptations suggested by the treatment algorithm for the successive second infusion. Four patients possessed undetectable infliximab levels and positive ATI status at baseline. After the second infusion, there were 29 (88%) patients in remission at the third infusion. All of this resulted in an annual drug cost reduction of &OV0556;47 026 (7.4%). CONCLUSION: Our developed treatment algorithm of infliximab led to optimization of infliximab therapy in IBD patients by increasing remission rates and reducing drug costs.
Assuntos
Algoritmos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Adulto , Anticorpos/sangue , Estudos de Coortes , Custos de Medicamentos , Feminino , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/economia , Fármacos Gastrointestinais/imunologia , Humanos , Infliximab/sangue , Infliximab/economia , Infliximab/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108 erythrocytes and 3525 pmol/8 × 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.