Exploring the role of oxidative stress and the effect of N-acetylcysteine in thiopurine-induced liver injury in inflammatory bowel disease: A randomized crossover pilot study.

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N-acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N-acetylcysteine decreased myeloperoxidase concentrations (33.6-24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S-methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2-isoprostanes (101-157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N-acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine-induced increase of serum liver tests.

Neonatal pain score after use of paracetamol: Is there a relationship with serum trough concentration at steady state in preterm and term neonates?

OBJECTIVE: An easy to establish and patient-friendly biomarker to guide dosing of paracetamol in neonates is currently not available. The aim of this study was to determine the potential association between the serum trough concentration and area under the curve (AUC) of paracetamol at steady state and differences in pain scores in preterm and term neonates. MATERIALS AND METHODS: A retrospective observational study was performed, using an academic hospital database to identify neonates treated with intravenous or rectal paracetamol for at least 48 hours. At steady state, serum trough concentrations and the 24-hour AUC were determined. Pain was measured by COMFORTneo scores, before the 1st and 6th dose. Linear regression was performed to assess the association between serum trough concentration and 24-hour AUC and differences in pain scores. Subgroup analyses were performed for patients who received paracetamol due to a COMFORTneo score ≥ 14 (group 1) or who received prophylactic paracetamol because of upcoming surgery (group 2). RESULTS: 21 neonates were included. The median (interquartile range (IQR)) serum trough concentration of paracetamol before the 6th dose was 4.5 mg/L (2.7 - 8.5 mg/L). In subgroup 1, the median (IQR) COMFORTneo scores before the 1st and 6th dose were 17 (16.5 - 20) and 12 (11 - 16.5), respectively. In subgroup 2, the median (IQR) scores were 9 (8 - 10) and 11 (9 - 12), respectively. The serum trough concentration and 24-hour AUC were not associated with reduced pain scores (p = 0.12 and p = 0.67, respectively). CONCLUSION: No association was found between the serum trough concentration and 24-hour AUC of paracetamol at steady state and differences in pain scores in preterm and term neonates. Future research is needed to prospectively determine a patient-friendly biomarker to optimize the treatment with paracetamol.

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.

Clinical validation of dried blood spot sampling in therapeutic drug monitoring of ciclosporin A in allogeneic stem cell transplant recipients: direct comparison between capillary and venous sampling.

BACKGROUND: The immunosuppressive drug ciclosporin A has a narrow therapeutic window and a large inter- and intraindividual pharmacokinetic variability. Therapeutic drug monitoring of ciclosporin is usually performed in ethylenediaminetetraacetic acid blood, obtained by venous sampling. Dried blood spot sampling (DBS) could be a useful alternative sampling method, which also easily allows multiple sampling, for example, for obtaining area under the curve. With DBS, capillary blood is obtained from a finger prick with an automatic lancet by the patients themselves, and the drop of blood is applied to sampling paper. This may limit the number and duration of hospital visits for these patients. METHODS: We describe a validation study in which venous and finger prick blood samples were collected at the same time. Venous sampling was performed by venipuncture, and the ethylenediaminetetraacetic acid blood samples were collected and stored at 4°C until analysis. Finger prick blood samples were collected using an automatic lancing device. The volume of the blood drops of patients was approximately 30 µL, and blood spots of about 10-mm diameter were produced. Paper disks with a diameter of 8 mm were punched out with an electromagnetic-driven hole puncher. DBS was compared with the routine assay in venous blood. The study population consisted of adult patients (18 years or older) who were treated with ciclosporin A and routinely monitored for adequate blood concentrations. RESULTS: Thirty-eight duplicate dried blood spots and venous samples were studied. Using weighted Deming regression, the slope was 1.01 with a standard error of 0.03 associated with an intercept of -9.0 (standard error = 5.9). These results indicate that there is no significant difference between the 2 sampling methods. For the medical decision level of 300 mcg/L, the bias was -4.7 mcg/L with a 95% confidence interval of -19.2 to 9.8 mcg/L. The Altman-Bland plot showed no difference between the 2 sampling methods. CONCLUSIONS: Our results demonstrate that DBS is a valid alternative for conventional venous sampling in allogeneic stem cell transplant recipients.

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT). • It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole). • Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS • A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIM To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODS The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTS Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h(-1) (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V(c) ) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t(lag) ) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3. Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction. CONCLUSIONS The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration-time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.

Effects of cyclosporine a on single-dose pharmacokinetics of intravenous itraconazole in patients with hematologic malignancies.

An open-label, clinical pilot study was performed to study the effect of cyclosporine A (CsA) on single-dose pharmacokinetics of itraconazole in patients with a hematologic malignancy. Patients (n = 10), admitted for allogeneic stem cell transplantation, received a single dose of 200 mg itraconazole in a 1-hour intravenous infusion during their treatment period before initiation of CsA. This was repeated during the period that CsA was administered and a steady-state concentration of CsA was achieved (trough whole blood level 200-400 ng/mL). After both administrations of itraconazole, serum pharmacokinetics of itraconazole and hydroxy (OH) itraconazole were determined during 24 hours. The results were compared with each patient acting as his or her own control. Exposure to itraconazole, as measured by the AUC[0-24h], was not significantly altered when combined with CsA. Large interindividual variations were observed in area under the concentration curve values among patients. In contrast, exposure to OH-itraconazole was significantly increased when itraconazole was coadministered with CsA (median increase of AUC[0-24h] 49%) with significant prolongation of T(max) and T1/2 (median increase of T(max) 37% and T1/2 176%). These differences may be the result of variability in affinity of itraconazole, OH-itraconazole, and CsA for the cytochrome P450 3A4 metabolic system and the occurrence of P-glycoprotein polymorphisms. In conclusion, exposure to OH-itraconazole, but not to itraconazole, is increased when itraconazole is coadministered with CsA. Although the interaction profile of itraconazole and CsA remains complex, these findings may be of importance in patients in whom monitoring of itraconazole serum levels is warranted, for example, in those with life-threatening fungal infections or in those who receive concurrent cytochrome inducers or inhibitors.