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Contains fulltext : 232472.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 229200.pdf (Publisher’s version ) (Open Access), AIMS: Vancomycin is an important antibiotic for critically ill patients with Gram-positive bacterial infections. Critically ill patients typically have severely altered pathophysiology, which leads to inefficacy or toxicity. Model-informed precision dosing may aid in optimizing the dose, but prospectively validated tools are not available for this drug in these patients. We aimed to prospectively validate a population pharmacokinetic model for purpose model-informed precision dosing of vancomycin in critically ill patients. METHODS: We first performed a systematic evaluation of various models on retrospectively collected pharmacokinetic data in critically ill patients and then selected the best performing model. This model was implemented in the Insight Rx clinical decision support tool and prospectively validated in a multicentre study in critically ill patients. The predictive performance was obtained as mean prediction error and relative root mean squared error. RESULTS: We identified 5 suitable population pharmacokinetic models. The most suitable model was carried forward to a prospective validation. We found in a prospective multicentre study that the selected model could accurately and precisely predict the vancomycin pharmacokinetics based on a previous measurement, with a mean prediction error and relative root mean squared error of respectively 8.84% (95% confidence interval 5.72-11.96%) and 19.8% (95% confidence interval 17.47-22.13%). CONCLUSION: Using a systematic approach, with a retrospective evaluation and prospective verification we showed the suitability of a model to predict vancomycin pharmacokinetics for purposes of model-informed precision dosing in clinical practice. The presented methodology may serve a generic approach for evaluation of pharmacometric models for the use of model-informed precision dosing in the clinic.

Item does not contain fulltext, BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug and mood stabilizer. A key characteristic of VPA is its high and saturable protein binding at higher concentrations. Although the unbound concentration of VPA is responsible for its pharmacological activity, total drug concentrations are monitored in routine clinical practice. Therapeutic drug monitoring (TDM) of unbound VPA is recommended for specific clinical situations. The goal of this study was to evaluate TDM requests for unbound VPA in clinical practice. METHODS: All TDM requests at our laboratory for unbound VPA in 2014 and 2015 were evaluated retrospectively. In patients with potentially toxic unbound VPA concentrations (ie, >12 mg/L), we evaluated whether toxicity was noted and whether the dose adjustment advice was followed. Total and unbound VPA concentrations were measured by means of a validated immunoassay. RESULTS: A total of 273 unbound VPA serum concentrations in 132 different patients were analyzed. The main reasons for unbound VPA TDM were decreased renal function (34%) and a low serum albumin (27%). The median (range) unbound VPA concentration was 9.8 (2.5-47.6) mg/L. In 49 patients (37%), the initial unbound VPA concentration was above the threshold of 12 mg/L, potentially resulting in toxicity. Only 6 of these 49 patients had elevated total VPA concentrations. Clinical toxicity was noted in 38 of the 49 patients (77.6%) with elevated unbound VPA concentrations. Toxicities included drowsiness (n = 26), decreased consciousness (n = 4), rigidity (n = 2), and confusion (n = 2). In 36 of the 38 patients with elevated unbound VPA concentrations and clinical toxicity, a dose reduction was applied. In 27 of 36 patients who had their dose reduced, dose reduction was associated with improvement or resolution of VPA toxicity. CONCLUSIONS: TDM of unbound VPA is an important tool to manage VPA therapy in selected, vulnerable patients.

Item does not contain fulltext, BACKGROUND: The yew (Taxus baccata) is a common evergreen tree containing the toxin taxine B. Between 42 and 91 g of yew leaf is lethal to a 70-kg adult. The objective of this article is to present an overview of findings in fatal yew intoxications. METHODS: A search using MeSH terms was performed in PubMed for yew intoxications in the period between January 1960 and August of 2016. RESULTS: We describe a total of 22 cases. Fatal intoxications can be divided into intoxications by leaves, by pulp, by bark and by yew tea. Recognizing yew tea intoxication is difficult since tea no longer contains any botanically recognisable parts. In autopsy and external examination no characteristic findings are reported, regarding the presence of parts of plants. CONCLUSIONS: Indications for yew tree intoxications at a post-mortem examination and autopsy are limited to finding parts of yew tree. The absence of recognisable parts can result in yew intoxications being overlooked. Therefore toxicological screening is recommended in unexplained deaths.

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Item does not contain fulltext, RATIONALE, AIMS AND OBJECTIVES: Renal dysfunction is highly prevalent in HIV-infected patients and may require dose adjustment of renally excreted antiretroviral drugs. The Modification of Diet in Renal Disease (MDRD)-4 formula is frequently used in daily practice to estimate patients' renal function. The aim of this systematic review was to assess the validity of the MDRD-4 formula in HIV-infected patients. METHOD: A systematic search in Pubmed and EMBASE was done to identify studies which compared MDRD-4 with measured glomerular filtration rate (mGFR) in HIV-infected patients. RESULTS: Five studies were included, which provided data from 464 HIV-infected patients with mean mGFR ranging from 87 to 118 ml/min/1.73 m(2). In all studies, results from the MDRD-4 gave an underestimation of the mGFR. Mean bias ((MDRD-4) - mGFR) ranged from -6 to -11 ml/min/1.73 m(2) across studies. The accuracy expressed in terms of P 30 ranged from 64 to 89 %. CONCLUSIONS: The MDRD-4 formula is as valid in HIV-positive as in HIV-negative patients. Because the available studies comprised mainly HIV-infected patients with mildly impaired to good renal function (GFR >/= 60 ml/min/1.73 m(2)), more research is needed to validate the MDRD-4 formula in HIV-infected patients with moderate to severe renal impairment.

Contains fulltext : 136062.pdf (Publisher’s version ) (Open Access), A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions.

Contains fulltext : 95624.pdf (publisher's version ) (Closed access), BACKGROUND: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005. METHODS: From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM. RESULTS: The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM. CONCLUSION: The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Contains fulltext : 89731.pdf (publisher's version ) (Closed access)

Contains fulltext : 88810.pdf (publisher's version ) (Closed access), BACKGROUND: To evaluate the potential drug-drug interaction between raltegravir and pravastatin. METHODS: This was an open-label, randomized, 3-period, cross-over, single-centre trial in 24 healthy volunteers. Subjects received the following treatments: pravastatin 40 mg every day for 4 days, raltegravir 400 mg twice a day for 4 days, and pravastatin 40 mg every day + raltegravir 400 mg twice a day for 4 days. The treatments were separated by washout periods of 10 days. On day 4 of each treatment period, blood samples for pharmacokinetics were collected throughout a 24-hour period. RESULTS: Geometric mean ratios (90% confidence interval) for pravastatin + raltegravir versus pravastatin alone were 0.96 (0.83 to 1.11) for AUC0-24 and 1.04 (0.85 to 1.26) for Cmax. The mean low-density lipoprotein cholesterol decrease after 4 days of pravastatin was 0.42 mmol/L both in the presence and the absence of raltegravir. The geometric mean ratio (90% confidence interval) AUC0-12, Cmax, and C12 for raltegravir + pravastatin versus raltegravir alone were 1.13 (0.77 to 1.65), 1.31 (0.81 to 2.13), and 0.59 (0.39 to 0.88), respectively. CONCLUSIONS: Raltegravir did not influence the pharmacokinetics or the short-term lipid-lowering effects of pravastatin, whereas pravastatin increased the Cmax but decreased the C12 of raltegravir. The effects of pravastatin on raltegravir pharmacokinetics are not likely to be clinically relevant.

Contains fulltext : 87324.pdf (publisher's version ) (Closed access), HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0-->t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

1 oktober 2010, Contains fulltext : 88741.pdf (publisher's version ) (Closed access), OBJECTIVES: To manage the interaction between fosamprenavir/ritonavir and posaconazole, we hypothesized that ritonavir can be replaced by posaconazole as an alternative booster of fosamprenavir with no significant influence on posaconazole pharmacokinetics. METHODS: This was an open-label, randomized, three period, cross-over, single-centre trial in 24 healthy volunteers. All subjects received the following three treatments for 10 days, separated by washout periods of 17 days: posaconazole 400 mg twice daily; fosamprenavir/ritonavir 700/100 mg twice daily; posaconazole 400 mg twice daily with fosamprenavir 700 mg twice daily. RESULTS: Twenty subjects completed the trial. Geometric mean ratios (GMR; +90% confidence interval) of posaconazole AUC and C(max) when taken with fosamprenavir versus posaconazole alone were 0.77 (0.68-0.87) and 0.79 (0.71-0.89), respectively. The GMRs of amprenavir AUC and C(max) when taken as fosamprenavir and posaconazole versus fosamprenavir/ritonavir were 0.35 (0.32-0.39) and 0.64 (0.55-0.76), respectively. No serious adverse events were reported during the trial. CONCLUSION: Unboosted fosamprenavir should not be used concomitantly with posaconazole.

26 november 2010, Promotor : Hekster, Y.A. Co-promotores : Burger, D.M., Richter, C., Contains fulltext : 82961.pdf (publisher's version ) (Open Access)

Contains fulltext : 80842.pdf (publisher's version ) (Closed access)

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Contains fulltext : 81310.pdf (publisher's version ) (Closed access), The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48-hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration-time curve (AUC(0-->48)) and peak plasma concentration (C(max)) for raltegravir + lamotrigine versus lamotrigine alone were 0.99 (0.96-1.01) and 0.94 (0.89-0.99), respectively. The mean ratio of the AUC(0-->48) of lamotrigine-2N-glucuronide to lamotrigine was similar when lamotrigine was taken alone (0.35) or when taken with raltegravir (0.36). Raltegravir does not influence the glucuronidation of lamotrigine.

Contains fulltext : 79598.pdf (publisher's version ) (Closed access), BACKGROUND: Co1nflicting data exist regarding the effect of efavirenz (EFV) plasma concentrations on central nervous system (CNS) toxicity. We aimed to determine whether patients with high EFV plasma concentrations have an increased likelihood of toxicity-driven EFV discontinuations. METHODS: EFV plasma concentrations were measured from patients in the EuroSIDA study starting EFV after 1 January 1999. Patients with a plasma concentration available were divided into those that discontinued EFV because of any toxicity or by the choice of the patient or physician within 2 years (TOXPC group) and those that continued EFV for > or = 2 years (no toxicity group). Multivariable logistic regression modelling was used to investigate the effects of the EFV plasma concentration and those of other potentially relevant factors on the risk of toxicity-induced EFV discontinuations. RESULTS: A total of 843 patients were included. Of these patients, 138 patients (16.4%) discontinued EFV because of TOXPC and 705 (83.6%) patients continued EFV for 22 years. A total of 20 (14.5%) patients in the TOXPC group had high EFV plasma concentrations (>4.0 mg/l) compared with 99 (14.0%) patients in the no toxicity group (P = 0.890). A positive hepatitis C status (P = 0.026), but not the EFV plasma concentration, was an independent predictor of toxicity-driven EFV discontinuations. CONCLUSIONS: No association was found between EFV plasma concentrations and the risk of EFV discontinuations because of (CNS) toxicity. This result questions the designation of EFV plasma concentrations >4.0 mg/l as being 'toxic', at least when defined by treatment discontinuation.

Contains fulltext : 69459.pdf (publisher's version ) (Closed access)