Nederlands Platform voor Farmaceutisch Onderzoek

Het Nederlands Platform voor Farmaceutisch Onderzoek (NPFO) presenteert onderzoek in de farmaceutische wetenschappen, zoals medicatieveiligheid, patiëntenzorg, formulering, (bio)analyse, (klinische) farmacologie en casuïstiek.

Hoge treosulfanblootstelling is geassocieerd met vroege toxiciteit bij stamceltransplantatie bij kinderen

M.Y.E.C. van der Stoep a*, M.H. ten Brink b, D.J.A.R. Moes a, H.J. Guchelaar a, J. Zwaveling a en A.C. Lankester c

Lees abstract

High treosulfan exposure is associated with early toxicity in paediatric hematopoietic stem cell transplantation

BACKGROUND

Treosulfan-based conditioning is increasingly employed in paediatric hematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unclear.

OBJECTIVE

To study treosulfan pharmacokinetics in relation to regimen-related toxicity and early clinical outcome in paediatric patients.

DESIGN

This research was conducted in a multicentre prospective observational study.

METHODS

Patients undergoing a transplantation in the paediatric transplant units in Leiden and Rome between June 2011 and July 2016 and receiving a treosulfan-based conditioning regimen for malignant and non-malignant indications, were included. Two blood samples were collected on day 1 to determine the area under the concentration-time curve (AUC) of treosulfan, calculated with a two-compartment pharmacokinetic model. The relationship between AUC and early toxicity was characterised using logistic regression.

RESULTS

A total of 77 patients were included. Mean treosulfan exposure on day 1 was 1744 ± 795 mg*hr/L (for children < 1 year of age receiving 10 g/m2) and 1561 ± 511 mg*hr/L (for children ≥ 1 year of age receiving 14 g/m2), with an inter-individual variability of 56% and 33%, respectively. High treosulfan exposure (> 1650 mg*hr/L) was associated with an increased risk of mucosal (odds ratio [OR] 4.40; 95% confidence interval [95% CI] 1.19-16.28, P = 0.026) and skin toxicity (OR 4.51; 95% CI 1.07-18.93, P = 0.040). No correlation was found between treosulfan exposure and the early clinical outcome parameters engraftment and acute graft-versus-host disease.

CONCLUSION

Our study provides the first evidence in a large cohort of paediatric patients for high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.

Rubriek: Korte bijdrage
Identificatie: 2018;3:a1675
Datum: 6 juni 2018

Dossiervoering van farmacogenetische uitslagen: een implementatieonderzoek in de Haagse regio

H.L. van den Hoek ab*, E.E. Roelofsen ab, R. Verheul cd, M. Veuger ce, E.B. Wilms af en L.E. Visser af

Lees abstract

Pharmacogenetic results in the patient’s record: an implementation survey in The Hague

BACKGROUND

Pharmacogenetic testing is becoming increasingly important as it is used in prevention of severe adverse drug reactions, and for optimization of pharmacological therapy for patients with an unexpected response to drugs. In our health care system pharmacogenetics has been introduced since a couple of years. However, the traceability of the pharmacogenetics status in electronic patient files is limited.

OBJECTIVE

To assess, improve and evaluate the process of recording information on the patient’s pharmacogenetic status within the hospital setting.

METHODS

This implementation survey was conducted in two hospitals in The Hague, with an assessment before implementation of structural recording of the pharmacogenetic status in 2015 and an evaluation after implementation in 2017. All patients with a request for pharmacogenetic testing by a physician affiliated with one of the hospitals were included. For each patient we collected data in electronic patient files. The primary outcome was the percentage of patients with a registration of the pharmacogenetic result, both wild-type and mutation, in the hospital information system on patient level.

RESULTS

Of the 193 patients included, none (0%) had their pharmacogenetic results reported in the hospital information system prior to implementation, compared to respectively 94,4% (17 of 18 patients) of the Haaglanden Medisch Centrum and 58,3% (42 of 72 patients) of the HagaZiekenhuis after implementation.

CONCLUSION

In this study 94,4% of the patients from the Haaglanden Medisch Centrum and 58,3% of the patients from the HagaZiekenhuis, had their pharmacogenetic status available in the hospital information system after implementation. Further revisions and research is needed to optimise the process and determine the influence on medication safety.

Rubriek: Korte bijdrage
Identificatie: 2018;3:a1674
Datum: 6 juni 2018

Meerderheid van de intensivecarepatiënten behandeld met ciprofloxacine bereikt de farmacodynamische streefwaarde niet

A. Abdulla a*, N.G.M. Hunfeld ab, A. Dijkstra c, S. Duran c, D.A.M.P.J. Gommers b, J.W. Mouton d, T. van Gelder ae en B.C.P. Koch a

Lees abstract

A majority of the ICU patients treated with ciprofloxacin does not achieve the pharmacodynamic target

BACKGROUND

Traditional antibiotic dosing is not designed for patients at the intensive care unit, as the extreme pharmacokinetic behaviour of drugs in critically ill patients threatens the achievement of optimal antibiotic treatment outcomes. For severe infections, the pharmacodynamic target (PDT) of ƒAUC0-24/MIC ≥ 100 has been proposed.

OBJECTIVE

In this study, we examine the PDT attainment of empirical dosing regimens of ciprofloxacin in critical ill patients and patient characteristics associated with the failure to achieve the PDT.

DESIGN

A prospective observational PK/PD study was performed at the ICUs of Erasmus MC and Maasstad Hospital, Rotterdam.

METHODS

Based on optimal sampling, five separate 5 mL samples were taken at various time points. Non-compartmental PK analysis was performed. The percentage PDT attainment was the primary endpoint. As a secondary endpoint, patient characteristics associated with the non-achievement of the PDT were evaluated using multivariate analysis.

RESULTS

A total of 43 ICU patients receiving intravenous ciprofloxacin were included in this study. The median age was 66 years, APACHE II score was 22 and creatinine clearance rate was 58 mL/min. The median ƒAUC0-24 and Cmax were 29.9 mg•h/L and 3.0 mg/L, respectively. The proportion of patients achieving the PDT was 16.3%. Using multivariate analysis, an increase of the body mass index, creatinine clearance rate and albumin were found to be predictive of a decreased ƒAUC0-24/MIC ratio.

CONCLUSION

An empirical approach of ciprofloxacin dosing results in poor target attainment in the majority of the ICU patients. At present, TDM of ciprofloxacin is not used as a routine intervention. We believe that should be changed, because of the high variability in PK parameters in critically ill patients.

Rubriek: Korte bijdrage
Identificatie: 2018;3:a1672
Datum: 6 juni 2018

De invloed van een veranderde Thyrax-verpakking op kwaliteit van leven

Bob Wilffert

Rubriek: Referaat
Identificatie: 2018;3:e1659
Datum: 4 mei 2018

Switchen van Remicade naar biosimilar bij inflammatoire darmziekten

Bob Wilffert

Rubriek: Referaat
Identificatie: 2018;3:e1660
Datum: 4 mei 2018

Acute, toxicologische screening wordt relevanter door uitbreiding van het standaardpanel van de drugs of abuse point-of-care test met gammahydroxyboterzuur en ketamine

J.A.J. van der Schaar a*, M.E. Attema-de Jonge b, F.M.J. Gresnigt c en E.J.F. Franssen b

Lees abstract

Acute, toxicological screening becomes more relevant by addition of GHB and ketamine to the standard test panel of the drugs of abuse point-of-care test

BACKGROUND

For diagnosis and treatment in the acute setting, it is crucial to know whether the patient’s clinical status might be explained by the effects of drugs.

OBJECTIVE

To determine how many drugs were detected by comprehensive toxicological screening, that could not be detected with a drugs of abuse point-of-care test (DOA-POCT). Furthermore, we determined in how many patients comprehensive toxicological screening did provide additional clinically relevant information on diagnosis and patient care, and which drugs were responsible for this.

DESIGN

In this prospective study, patients were included for whom a DOA-POCT was performed and residual urine and serum samples were available.

METHODS

DOA-POCTs were performed using the Triage TOX Drug Screen. Comprehensive toxicological screenings were performed using the Toxtyper LC-MSN method and two GC-FID methods for alcohols and gamma-hydroxybutyric acid (GHB), respectively. The clinical relevance of the comprehensive toxicological screening results on diagnosis and patient care decisions were quantified.

RESULTS

100 patients were included. Comprehensive toxicological screening identified 234 drugs in 91 patients that were not identified by DOA-POCT. On the other hand, DOA-POCT identified 34 DOA that were not identified by comprehensive toxicological screening. 7% of comprehensive toxicological screening results were found to be clinically relevant for the diagnosis, with GHB and ketamine being the drugs involved. Another 38% strengthened confidence in diagnosis and patient care decisions.

CONCLUSION

GHB and ketamine should be added to the panel of drugs we screen with the DOA-POCT in our acute, hospital setting.

Rubriek: Oorspronkelijk artikel
Identificatie: 2018;3:a1671
Datum: 4 mei 2018

Het effect van maagzuurremmende geneesmiddelen op de behandeluitkomst met abirateronacetaat in patiënten met gemetastaseerde castratieresistente prostaatkanker

C. Bethlehem ab*, G.E. Benoist b, A. Colbers b, D.M. Burger b en N.P. van Erp b

Lees abstract

The effect of acid reducing agents on treatment outcome with abiraterone acetate in patients with metastatic castration-resistant prostate cancer

BACKGROUND

Abiraterone acetate is registered for pre- and postchemotherapy treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate shows poor bioavailability and the solubility rapidly declines at pH > 1. Acid reducing agents (ARA’s), e.g. proton pump inhibitors, H2 antagonists, or antacids, may affect abiraterone uptake due to the poor solubility of abiraterone acetate at pH exceeding 1. The exposure to abiraterone is critical since a relation between abiraterone exposure, PSA decrease and overall survival was shown in patients treated with this drug.

OBJECTIVE

To investigate whether acid reducing agents have an effect on the efficacy of abiraterone acetate in patients with mCRPC.

DESIGN AND METHODS

In this retrospective database study, mCRPC-patients who started treatment with abiraterone acetate in the Radboudumc, Nijmegen from September 2011 till May 2016 were identified. Data e.g. use of abiraterone, co-medication, use of acid reducing agents, and PSA were collected. PSA progression, progression-free survival, time to nadir PSA, PSA in week 12, and reaching 50 percent decrease in PSA are compared in patients pre- and postchemotherapy with or without acid reducing agents during therapy with abiraterone acetate.

RESULTS

No difference in outcome is shown for PSA progression in patients in time with or without ARA’s prechemotherapy (9.0 versus 8.5 months; hazard ratio [HR] 0.9, 95%-confidence interval [95%-CI] 0.6-1.6) and postchemotherapy (8.2 versus 8.0; HR 1.3, 95%-CI 0.5-3.3). Progression-free survival, time to nadir PSA, PSA in week 12, and reaching 50 percent decrease in PSA did not show statistically significant differences.

CONCLUSION

The use of acid reducing agents is not associated with a decreased effect of abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

Rubriek: Korte bijdrage
Identificatie: 2018;3:a1673
Datum: 4 mei 2018

Vemurafenib en dabrafenib in combinatie met radiotherapie en het risico op verergerde radiotoxiciteit

A.H.M. de Vries Schultink a*, J. Koomen b, B. van Triest c, J.J.M.A. Hendrikx a, J.B.A.G. Haanen d, J.H. Beijnen ae en A.D.R. Huitema af

Lees abstract

Vemurafenib and dabrafenib in combination with radiotherapy and the risk of aggravated radiotoxicity

OBJECTIVE

Firstly, to evaluate radiotoxicity in a cohort with patients receiving both radiotherapy and a BRAF inhibitor (BRAFi). Secondly, to identify whether the BRAFi used, dabrafenib or vemurafenib, is related to radiotoxicity.

DESIGN

This study is a retrospective cohort study, reflecting daily clinical practice.

METHODS

In total, 119 patients were included in this analysis. Patients were treated with vemurafenib (n = 42) or dabrafenib (n = 77) in combination with radiotherapy within a time frame of two months. The incidence of induced radiotoxicity was compared between both groups with a Fisher’s exact test. A logistic regression analysis was performed to identify potential factors related to the probability of experiencing induced radiotoxicity: type of BRAFi, combination therapy with a MEK inhibitor, age, sequence of treatment and location, cumulative radiation dose and total incidences of radiotherapy.

RESULTS

Induced radiotoxicity was seen in 6.7% of all patients. In the vemurafenib group 4.8% of patients experienced induced radiotoxicity compared to 7.8% in the dabrafenib group, this difference was not significant (P = 0.71). The logistic regression analysis revealed that none of the analyzed factors were related to the probability of experiencing induced radiotoxicity.

CONCLUSION

Both vemurafenib and dabrafenib administered in combination with radiotherapy induced radiotoxicity. No preference for dabrafenib over vemurafenib exists. The induced toxicity was manageable and did not lead to fatalities in this cohort. No predictive factors could be identified.

Rubriek: Oorspronkelijk artikel
Identificatie: 2018;3:a1669
Datum: 29 maart 2018

Beloop en behandeling van een intoxicatie met baclofen

D. Mitrovic a*, A. Assendorp b, C. Bethlehem c, H. de Boer d en E. ten Hoeve e

Lees abstract

Course and treatment of baclofen intoxication

INTRODUCTION

The number of reports on baclofen intoxication has increased in recent years. This is related to the increasing use of baclofen in the treatment of alcohol and gamma-hydroxybutyric acid withdrawal and as recreative drug.

DESCRIPTION

A 27-year-old man with a history of psychiatric comorbidity and an addiction problem was brought to the emergency department (ED) in an unresponsive state (EMV score 3) after an attempted suicide with medication. After heteroanamnesis, he was diagnosed with an intoxication of 850 mg baclofen, 2.5 liters’ beer and an unknown amount of heroine. He was intubated because of respiratory failure. Besides, activated charcoal in combination with a laxative was administered. Morphine and midazolam were administered to prevent withdrawal symptoms. The EMV score improved 30 hours after admission and he was detubated 60 hours after admission.

DISCUSSION AND CONCLUSION

The treatment of a baclofen intoxication consists of supportive care. This case demonstrates the importance of keeping a baclofen intoxication in mind in the differential diagnoses when a comatose or confused patient with addiction problems is brought in at the ED. Baclofen levels cannot be determined with standard drug screening so considering specific laboratory testing is necessary to detect baclofen intoxication.

Rubriek: Casuïstische mededeling
Identificatie: 2018;3:a1670
Datum: 28 maart 2018

De invloed van SGLT-2-remmers op de nierfunctie en cardiovasculaire risico’s

Harm Geers ab*

Lees abstract

The influence of SGLT-2 inhibitors on kidney function and cardiovascular risks

BACKGROUND

SGLT-2 inhibitors are a new treatment option in type 2 diabetes mellitus. The EMPA-REG OUTCOME study showed improved outcomes in mortality and cardiovascular disease in patients treated with empagliflozine. A subanalysis on microvascular outcomes showed that empagliflozine protected renal function by lowering the intraglomerular pressure. In June 2016 the FDA issued a warning for acute kidney injury associated with canagliflozine and dapagliflozine use.

OBJECTIVE

To find an explanation for the mechanisms behind renal protection, reduced cardiovascular events and mechanisms that may cause acute kidney failure in SGLT-2 inhibitors.

METHODS

Literature was reviewed to find information about the possible mechanisms for renal protection and renal injury. Human, animal as well as in vitro studies that elucidated possible pharmacological mechanisms behind the effects of SGLT-2 inhibitors on renal function, the cardiovascular system, or the cause of renal injury were considered eligible for this study.

RESULTS

A possible pharmacological explanation for the effect of SGLT-2 inhibitors on renal protection was found in several studies. It was also possible to explain effects of the cardiovascular system and two possible causes of renal injury were found.

CONCLUSION

Based on the mechanism of action of SGLT-2 inhibitors, it was possible to make a recommendation for pharmacists to avoid combination of SGLT-2 inhibitors and drugs that decrease renal function, especially the combination of diuretics and/or nonsteroidal anti-inflammatory drugs with SGLT-2 inhibitors. The combination of SGLT-2 inhibitors with ACE inhibitors may also reduce renal function but is beneficial in patients with (micro)albuminuria.

Rubriek: Oorspronkelijk artikel
Identificatie: 2018;3:a1657
Datum: 28 maart 2018

Onderzoek naar zelfmanagement bij astma en goed geneesmiddelengebruik (SMARAGD-studie): een pilotonderzoek

Esther Kuipers ab*, Michel Wensing ac, Peter de Smet ad en Martina Teichert ae

Lees abstract

Self-management research of asthma and good drug use (SMARAGD study): a pilot trial

BACKGROUND

Community pharmacists play an important role in supporting patients for optimal drug use.

OBJECTIVE

To assess the effectiveness of monitoring in asthma patients with inhaled corticosteroids (ICS) on disease control.

DESIGN

Asthma patients using ICS were invited from two intervention (IG) and two control pharmacies (CG).

METHODS

Participating patients completed questionnaires at the study start and at 6-month follow-up, including the Control of Allergic Rhinitis and Asthma Test (CARAT) questionnaire. IG patients completed the CARAT questionnaire every two weeks and received counselling on disease management, ICS adherence, and inhalation technique when scores were suboptimal, deteriorating, or absent. For Turbuhaler users, additional electronic monitoring (EMI) was available, with daily alerts for ICS intake. As the primary outcome, CARAT scores at follow-up were compared between IG and CG using linear regression. As secondary outcome, refill adherence was compared using logistic regression.

RESULTS

From March to July 2015, we enrolled 39 IG and 41 CG patients. At follow-up, CARAT scores did not differ between IG and CG (-0.19; 95% confidence interval [95% CI], -2.57 to 2.20), neither did patient numbers with ICS adherence > 80% (0.82; 95% CI, 0.28-2.37). Among EMI users, CARAT scores did not differ, but ICS adherence > 80% showed a 4.52-fold increase (95% CI, 1.56-13.1) compared with EMI nonusers.

CONCLUSION

Among community-dwelling asthma patients, pharmacist monitoring did not affect CARAT scores, but EMI use showed improved ICS refill adherence.

Rubriek: Oorspronkelijk artikel
Identificatie: 2018;3:a1667
Datum: 8 maart 2018

De ziekenhuisapotheker als behandelaar bij intoxicaties: evaluatie van het zorgpad intoxicaties

Manon Bakker *, Douwe van der Meer, Daphne Bertholee en Peter ter Horst

Lees abstract

The hospital pharmacist as a member of the multidisciplinary team in the treatment of the intoxicated patient

OBJECTIVE

To investigate the role of the hospital pharmacist as a member of the multidisciplinary team in the treatment of intoxicated patients.

DESIGN AND METHODS

This study is a retrospective observational study. Electronic patient records of all patients admitted to the Isala hospital in Zwolle with an intoxication in 2016 were analysed. We determined the number of cases in which the hospital pharmacist was consulted and if this was recorded in the patient record. Furthermore, the influence of drug-specific local treatment protocols on the number of consultations was assessed. The Emergency Department (ED) doctors were questioned about their experiences regarding the consultation of the hospital pharmacist.

RESULTS

A total of 367 intoxicated patients were admitted to the ED. In 300 of these cases the patients were intoxicated with another agent than alcohol. In 40% of these cases the hospital pharmacist was consulted, which was recorded in the electronic patient record in 71% of these cases. Four patients died as a result of their intoxication. The presence of a drug-specific local treatment protocol had no effect on the number of consultations of the hospital pharmacist. The ED doctors were satisfied with the hospital pharmacist as a member of the multidisciplinary team. The hospital pharmacist actively participates in advising about the appropriate treatment of the individual intoxicated patient.

CONCLUSION

Hospital pharmacists are valued by the ED doctors as a member of the multidisciplinary team in the treatment of intoxicated patients.

Rubriek: Oorspronkelijk artikel
Identificatie: 2018;3:a1668
Datum: 8 maart 2018

Contact

Redacteur / secretaris
Maarke Roelofs

(070) 373 71 09 npfo@npfo.nl