Publications by authors named "Nils Tore Vethe"

30 Publications

  • Page 1 of 1

Fast and reliable quantification of busulfan in blood plasma using two-channel liquid chromatography tandem mass spectrometry: Validation of assay performance in the presence of drug formulation excipients.

J Pharm Biomed Anal 2021 Sep 17;203:114216. Epub 2021 Jun 17.

Department of Pharmacology, Oslo University Hospital, Oslo, Norway. Electronic address:

A fast and reliable method based on two-channel liquid chromatography coupled to tandem mass spectrometry was developed and successfully validated for quantification of busulfan. The drug vehicle polyethylene glycol 400 was quantified simultaneously in patient samples. The sample preparation consisted of simple protein precipitation using a mixture of methanol and zinc sulphate containing busulfan-d8 as internal standard. Chromatographic separation was performed on a short biphenyl column (30 mm × 3.0 mm, 5 μm particles) using a step gradient from 30 % to 85 % methanol, ensuring co-elution of the analyte and internal standard. Quantification was performed using the mass transition of 264.1 > 151.1 for busulfan and 272.1 > 159.1 for the internal standard. Using only 20 μL of plasma sample, the lower limit of quantification was 25 ng/mL. Signal to noise ratio at the lower limit of quantification exceeded 300. The assay performance was not adversely affected by matrix effects originating from drug formulation excipients or other sample components. The coefficient of variation was ≤4 % and the mean accuracy 101-108 % across the calibration range 25-5 000 ng/mL. Chromatographic run time was 2 min and 8 s, allowing an effective run-time of 1 min and 10 s when using two alternating LC-channels. The assay has been implemented in routine practice with accreditation according to the ISO 15189 standard, and performs well in external quality control assessments. We present for the first time that shortly after an IV infusion of busulfan, the plasma levels of polyethylene glycol 400 may be in the range of 400-800 mg/L. The presence of these levels of detergent in patient samples may have detrimental effects on assay performance in LC-MS/MS, not limited to busulfan assays. This may be a concern for any LC-MS/MS analysis performed on samples collected within the first 24 h after an IV infusion of busulfan.
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http://dx.doi.org/10.1016/j.jpba.2021.114216DOI Listing
September 2021

Increased systemic exposure of once-daily tacrolimus in renal transplant recipients on marine omega-3 fatty acid supplementation.

Transpl Int 2021 07 8;34(7):1322-1324. Epub 2021 Jun 8.

Division of Medicine, Department of Renal Medicine, Akershus University Hospital, Lørenskog, Norway.

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http://dx.doi.org/10.1111/tri.13917DOI Listing
July 2021

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Ther Drug Monit 2021 04;43(2):150-200

INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France.

Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
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http://dx.doi.org/10.1097/FTD.0000000000000871DOI Listing
April 2021

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients-A Cross-Validation Study.

Ther Drug Monit 2021 06;43(3):371-375

Department of Pharmacology, Oslo University Hospital; and.

Background: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population.

Methods: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography-tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing-Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference.

Results: A total of 39 SOT patients aged 4-18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6-13.6) mcg/L, with a difference between VAMS and venous blood samples of -0.2 ± 0.7 mcg/L. The relative mean difference was -1.3% [95% confidence interval (CI), -5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8-19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of -2.5% (95% confidence interval, -8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference.

Conclusions: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.
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http://dx.doi.org/10.1097/FTD.0000000000000873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115734PMC
June 2021

Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.
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http://dx.doi.org/10.3390/cancers12123628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761836PMC
December 2020

Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.

Clin Transl Sci 2020 11 11;13(6):1327-1335. Epub 2020 Jul 11.

Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.
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http://dx.doi.org/10.1111/cts.12833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719361PMC
November 2020

Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side-effects: a randomized, double blinded crossover trial.

Eur Heart J Cardiovasc Pharmacother 2020 Jul 1. Epub 2020 Jul 1.

Department of Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Dronninggata 28, Drammen, Norway.

Aims: To estimate the effect of atorvastatin on muscle symptom intensity in coronary heart disease (CHD) patients with self-perceived statin-associated muscle symptoms (SAMS) and to determine the relationship to blood levels of atorvastatin and/or metabolites.

Methods And Results: A randomized multi-center trial consecutively identified 982 patients with previous or ongoing atorvastatin treatment after a CHD event. Of these, 97 (9.9%) reported SAMS and 77 were randomized to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was the individual mean difference in muscle symptom intensity between the treatment periods, measured by visual-analogue scale (VAS) scores. Atorvastatin did not affect the intensity of muscle symptoms among 71 patients who completed the trial. Mean VAS difference [statin-placebo] was 0.31 (95% CI -0.24-0.86). The proportion with more muscle symptoms during placebo than atorvastatin was 17% (n = 12), 55% (n = 39) had the same muscle symptom intensity during both treatment periods whereas 28% (n = 20) had more symptoms during atorvastatin than placebo (confirmed SAMS). There were no differences in clinical or pharmacogenetic characteristics between these groups. The levels of atorvastatin and/or metabolites did not correlate to muscle symptom intensity among patients with confirmed SAMS (Spearmans rho ≤0.40, for all variables).

Conclusion: Re-challenge with high-intensity atorvastatin did not affect the intensity of muscle symptoms in CHD patients with self-perceived SAMS during previous atorvastatin therapy. There was no relationship between muscle symptoms and the systemic exposure to atorvastatin and/or its metabolites. The findings encourage an informed discussion to elucidate other causes of muscle complaints and continued statin use.
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http://dx.doi.org/10.1093/ehjcvp/pvaa076DOI Listing
July 2020

Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation.

Br J Clin Pharmacol 2020 06 16;86(6):1100-1112. Epub 2020 Feb 16.

Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Aims: To explore the pharmacodynamics of mycophenolic acid (MPA) through inosine monophosphate dehydrogenase (IMPDH) capacity measurement and purine levels in peripheral blood mononuclear cells (PBMC) longitudinally during the first year after renal transplantation (TX).

Methods: PBMC were isolated from renal recipients 0-4 days prior to and 6-9 days, 5-7 weeks and 1 year after TX (before and 1.5 hours after dose). IMPDH capacity and purine (guanine and adenine) levels were measured in stimulated and nonstimulated PBMC.

Results: Twenty-nine patients completed the follow-up period, of whom 24 received MPA. In stimulated PBMC, the IMPDH capacity (pmol 10 cells min ) was median (interquartile range) 127 (95.8-147) before TX and thereafter 44.9 (19.2-93.2) predose and 12.1 (4.64-23.6) 1.5 hours postdose across study days after TX. The corresponding IMPDH capacity in nonstimulated PBMC was 5.71 (3.79-6.93), 3.35 (2.31-5.62) and 2.71 (1.38-4.08), respectively. Predose IMPDH capacity in nonstimulated PBMC increased with time, reaching pre-TX values at 1 year. In stimulated PBMC, both purines were reduced before (median 39% reduction across days after TX) and after (69% reduction) dose compared to before TX. No alteration in the purine levels was observed in nonstimulated PBMC. Patients needing dose reductions during the first year had lower pre-dose IMPDH capacity in nonstimulated PBMC (1.87 vs 3.00 pmol 10 cells min , P = .049) at 6-9 days.

Conclusion: The inhibitory effect of MPA was stronger in stimulated PBMC. Nonstimulated PBMC became less sensitive to MPA during the first year after TX. Early IMPDH capacity appeared to be predictive of dose reductions.
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http://dx.doi.org/10.1111/bcp.14218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256122PMC
June 2020

Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells.

Cell Transplant 2019 Dec 12;28(12):1603-1613. Epub 2019 Sep 12.

Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden.

Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.
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http://dx.doi.org/10.1177/0963689719872488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923545PMC
December 2019

Pharmacogenetics in personalised drug therapy.

Tidsskr Nor Laegeforen 2019 May 6;139(8). Epub 2019 May 6.

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http://dx.doi.org/10.4045/tidsskr.19.0055DOI Listing
May 2019

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report.

Ther Drug Monit 2019 06;41(3):261-307

Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
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http://dx.doi.org/10.1097/FTD.0000000000000640DOI Listing
June 2019

Statin-associated muscle symptoms in coronary patients: design of a randomized study.

Scand Cardiovasc J 2019 Jun 13;53(3):162-168. Epub 2019 May 13.

a Department of Medicine, Drammen Hospital , Vestre Viken Trust , Drammen , Norway.

. Estimate the effect of atorvastatin on muscular symptom intensity in coronary patients with subjective statin-associated muscle symptoms (SAMS) and to determine the association with blood levels of atorvastatin and its metabolites, to obtain an objective marker for true SAMS. . A randomized, double-blinded, cross-over study will include 80 coronary patients with subjectively reported SAMS during ongoing atorvastatin therapy or previous muscle symptoms that led to discontinuation of atorvastatin. Patients will be randomized to 7-weeks treatment with atorvastatin 40 mg/day in the first period and matched placebo in the second 7-weeks period, or placebo in the first period and atorvastatin in the second period. Each period is preceded by 1-week wash-out. A control group ( = 40) without muscle symptoms will have 7 weeks open treatment with atorvastatin 40 mg/day. Blood samples will be collected at baseline and at the end of each treatment period, and muscular symptoms will be rated by the patients weekly using a Visual Analogue Scale (VAS). The primary outcome is the difference in aggregated mean VAS scores between the last three weeks of atorvastatin treatment and of placebo treatment. The main purpose is to develop an objective marker for true SAMS, by comparing SAMS associated with blinded atorvastatin treatment with blood concentrations of atorvastatin and its metabolites. Diagnostic and discrimination performance will be determined. . The study provides new knowledge on SAMS in coronary patients and may contribute to more personalized statin treatment and monitoring, fewer side-effects and consequently improved adherence and lipid management in future practice.
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http://dx.doi.org/10.1080/14017431.2019.1612085DOI Listing
June 2019

A Method for Direct Monitoring of Atorvastatin Adherence in Cardiovascular Disease Prevention: Quantification of the Total Exposure to Parent Drug and Major Metabolites Using 2-Channel Chromatography and Tandem Mass Spectrometry.

Ther Drug Monit 2019 02;41(1):19-28

Department of Pharmacology, Oslo University Hospital, Oslo.

Background: Low adherence to statin therapy remains a public health concern associated with poor prognosis in cardiovascular disease patients. A feasible method for statin adherence monitoring in clinical practice has yet to be developed. In this article, we describe a novel method designed for the direct monitoring of atorvastatin adherence based on the sum of parent drug and major metabolites in blood samples.

Methods: Acid and lactone forms of atorvastatin, 2-OH-atorvastatin, and 4-OH-atorvastatin were assayed. Plasma proteins were precipitated with an acidified mixture of methanol, acetonitrile, and aqueous zinc sulfate, and the supernatant was analyzed with 2-channel reversed-phase chromatography coupled to tandem mass spectrometry. Assay validation was performed according to the guidelines provided by the European Medicines Agency and the US Food and Drug Administration.

Results: The effective run time was 1 minute and 45 seconds per sample. Mean accuracy ranged from 92% to 110%, and coefficients of variation were ≤8.1% over the measurement ranges for individual compounds. The sum of acids and corresponding lactones was stable in clinical plasma samples kept at ambient temperature for up to 6 days after blood sampling (mean sum within 96.6%-101% of baseline).

Conclusions: A fast and reliable assay for the quantification of atorvastatin and its 5 major metabolites in clinical blood samples is reported. Limitations of preanalytical stability were solved using the sum of the acid and lactone forms. The assay is feasible for implementation in clinical practice, and the sum of parent drug and metabolites may be used for direct monitoring of atorvastatin adherence.
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http://dx.doi.org/10.1097/FTD.0000000000000578DOI Listing
February 2019

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients.

Ther Drug Monit 2019 02;41(1):11-18

Departments of Medical Biochemistry, Radiumhospitalet and.

Background: Belatacept (Nulojix; Bristol-Myers Squibb, New York, NY) is a biological immunosuppressive drug used for the prophylaxis of acute rejection after renal transplantation. Few studies have described belatacept pharmacokinetics, and the effect of therapeutic drug monitoring has not been investigated. We have developed a drug-capture assay (using drug target) to measure belatacept in serum and applied this assay in a pharmacokinetic study in renal transplant recipients.

Methods: CD80 was used to trap belatacept onto streptavidin-coated wells. Captured drug was quantified using Eu-labeled protein A and time-resolved fluorescence. The assay was applied in a pilot pharmacokinetic study in renal transplanted patients receiving belatacept infusions. Belatacept serum concentrations were determined at several time points between belatacept infusions. A simple population pharmacokinetic model was developed to visualize measured and predicted belatacept serum concentrations.

Results: The assay range was 0.9-30 mg/L with accuracy within 91%-99% and coefficients of variation ranging from 1.2% to 3.6%. Predilution extended the measurement range to 130 mg/L with an accuracy of 90% and coefficients of variation of 3.8%. Samples were stable during storage at 4°C for 15 days and during 2 freeze-thaw cycles. Belatacept concentrations were determined in a total of 203 serum samples collected during 26 infusion intervals from 5 renal transplant recipients. The population pharmacokinetic model visualized both measured and predicted concentrations.

Conclusions: We have developed an automated, accurate, and precise assay for the determination of belatacept serum concentrations. The assay was successfully applied in a pharmacokinetic study in renal transplant recipients receiving belatacept infusions.
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http://dx.doi.org/10.1097/FTD.0000000000000580DOI Listing
February 2019

BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): Rationale and design of a prospective, randomized, open, blinded end point study.

Am Heart J 2019 02 25;208:37-46. Epub 2018 Oct 25.

Department of Cardiology, Oslo University Hospital, Ullevaal and Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: Current guidelines on the use of β-blockers in post-acute myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF) are based on studies before the implementation of modern reperfusion and secondary prevention therapies. It remains unknown whether β-blockers will reduce mortality and recurrent MI in contemporary revascularized post-MI patients without reduced LVEF.

Design: BETAMI is a prospective, randomized, open, blinded end point multicenter study in 10,000 MI patients designed to test the superiority of oral β-blocker therapy compared to no β-blocker therapy. Patients with LVEF ≥40% following treatment with percutaneous coronary intervention or thrombolysis and/or no clinical signs of heart failure are eligible to participate. The primary end point is a composite of all-cause mortality or recurrent MI obtained from national registries over a mean follow-up period of 3 years. Safety end points include rates of nonfatal MI, all-cause mortality, ventricular arrhythmias, and hospitalizations for heart failure obtained from hospital medical records 30 days after randomization, and from national registries after 6 and 18 months. Key secondary end points include recurrent MI, heart failure, cardiovascular and all-cause mortality, and clinical outcomes linked to β-blocker therapy including drug adherence, adverse effects, cardiovascular risk factors, psychosocial factors, and health economy. Statistical analyses will be conducted according to the intention-to-treat principle. A prespecified per-protocol analysis (patients truly on β-blockers or not) will also be conducted.

Conclusions: The results from the BETAMI trial may have the potential of changing current clinical practice for treatment with β-blockers following MI in patients without reduced LVEF. EudraCT number 2018-000590-75.
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http://dx.doi.org/10.1016/j.ahj.2018.10.005DOI Listing
February 2019

Longitudinal Study of Tacrolimus in Lymphocytes During the First Year After Kidney Transplantation.

Ther Drug Monit 2018 10;40(5):558-566

Departments of Pharmacology and.

Introduction: Tacrolimus (TAC) is an immunosuppressive drug used after organ transplantation. Dosing is adjusted using whole blood (WB-TAC) measurements. Patients within the therapeutic WB-TAC window still experience rejections and adverse effects. Alternative monitoring methods are therefore warranted. The authors developed a method for measuring TAC in peripheral blood mononuclear cell (PBMC) isolates (PBMC-TAC) and performed a pharmacokinetic study in a cohort of kidney transplant patients during the first year after transplantation.

Methods: PBMCs were isolated from whole blood by gradient centrifugation. After methanol-based extraction, liquid chromatography with tandem mass spectrometry was used to determine TAC in the extract. PBMC-TAC was normalized to the number of cells and alternatively to the protein amount in cells. Predose and postdose (1.5 hours) samples from kidney transplant patients were collected at 1 week, 6 weeks, and 1 year after transplantation. WB-TAC was measured using immunoassay.

Results: The PBMC-TAC assay fulfilled the validation criteria of the European Medicines Agency guidelines. Twenty-nine patients completed the study. Predose PBMC-TAC was (median) 23 (1 week), 33 (6 weeks), and 27 pg/10 cells (1 year). Postdose PBMC-TAC was 44, 30, and 27 pg/10 cells at 1 week, 6 weeks, and 1 year after transplantation, respectively. Predose WB-TAC (median) was 5.0, 6.0, and 5.4 mcg/L, and postdose WB-TAC was 10.5, 8.3, and 9.1 mcg/L, respectively, at 1 week, 6 weeks, and 1 year after transplantation. Whole blood and PBMC-TAC correlated at all timepoints (rho 0.40-0.82, P < 0.05) except before dosage at 6 weeks. PBMC-TAC normalized to the number of cells, and the amount of protein was modestly correlated (rho 0.36-0.81, P < 0.056).

Conclusions: The correlation between WB-TAC and PBMC-TAC is modest during the first-year posttransplantation. Normalization of PBMC-TAC to cells or protein may yield different results. PBMC-TAC is increased 1.5 hours after dose at 1 week after transplantation, but not after 6 weeks or 1 year, indicating altered distribution kinetics.
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http://dx.doi.org/10.1097/FTD.0000000000000539DOI Listing
October 2018

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients-A Prospective Study.

Ther Drug Monit 2017 10;39(5):472-482

Departments of *Medical Biochemistry and †Pediatrics, Oslo University Hospital; ‡School of Pharmacy, University of Oslo; and §Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Background: Prednisolone is a standard component of immunosuppressive protocols in renal transplantation (Tx) and despite standardized treatment regimens, adverse side effects are still frequent. The aim of this study was to characterize the pharmacokinetics of prednisolone and prednisone in pediatric renal transplant recipients in the first 52 weeks post Tx, to describe the relationship between prednisolone and prednisone, and to investigate a possible relationship between the development of new-onset diabetes after Tx (NODAT) and glucocorticoid exposure.

Methods: Renal transplant recipients receiving prednisolone (n = 11, age 1-15 years) were included in this prospective open-label, descriptive, nonrandomized, and noninterventional study. Blood samples were drawn pre-Tx and during selected dose intervals (0, 1, 2, 4, 6, and 12 hours postdose; less frequent in children <10 kg) at 1, 2, 3, 4, 12, and 52 weeks post-Tx. Concentrations of prednisolone and cortisol, their inactive keto forms, plus methylprednisolone, were measured using a validated LC-MS/MS method. Genetic variants in the CYP3A4, CYP3A5, ABCB1, and HSD11B2 genes were analyzed using real-time polymerase chain reaction and Sanger sequencing. Correlation with NODAT was investigated.

Results: The patients displayed considerable intra- and inter-individual variability in prednisolone exposure, with up to 5-fold differences in the area under the concentration-time curve (AUC). There were up to 7-fold differences in prednisolone/prednisone AUC ratio between patients, and patients experiencing NODAT tended to have a higher ratio (>12) compared with patients without NODAT (<12). Genetic variants in CYP3A5 and ABCB1 were found, but due to the limited study population causality cannot be definitive.

Conclusions: The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.
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http://dx.doi.org/10.1097/FTD.0000000000000439DOI Listing
October 2017

Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human Islets In Vitro Compared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids.

J Diabetes Res 2016 18;2016:4196460. Epub 2016 Jan 18.

Department of Transplant Medicine, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway.

Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.
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http://dx.doi.org/10.1155/2016/4196460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739465PMC
December 2016

Drug target molecules to guide immunosuppression.

Clin Biochem 2016 Mar 8;49(4-5):411-8. Epub 2015 Oct 8.

Oslo University Hospital, Department of Pharmacology, Oslo, Norway.

The individual and interindividual variability of response to immunosuppressants combined with the prevailing concept of lifelong immunosuppression following any organ transplantation motivates the search for methods to further individualize such therapy. Traditional therapeutic drug monitoring, adapting dose according to concentrations in blood, targets the pharmacokinetic variability. It has been increasingly recognized, however, that there is also a considerable variability in the response to a given concentration. Attempts to overcome this variability in response include the efforts to identify relevant targets and methods for pharmacodynamic monitoring. For several of the currently used immunosuppressants there is experimental data suggesting markers that are relevant as indicators for individual monitoring of the effects of these drugs. There are also some clinical data to support these approaches; however what is generally missing, are studies that in a prospective manner demonstrates the benefits and effects on outcome. The monitoring of antithymocyte globulin by lymphocyte subset counts is actually the only well established example of pharmacodynamic monitoring. For drugs such as MPA and mTOR inhibitors, there are candidates such as IMPDH activity expression and p70SK6 phosphorylation status, respectively. The monitoring of CNIs using assays for NFAT RGE, either alone or combined with concentration measurements, is already well documented. Even here, some further investigations relating to the categories of organ transplant, combination of immunosuppressants etc. will be requested. Although some further standardization of the assay is warranted and there is a need for specific recommendations of target levels and how to adjust dose, the NFAT RGE approach to pharmacodynamic monitoring of CNIs may be close to implementation in clinical routine.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.10.001DOI Listing
March 2016

Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro.

Transpl Int 2015 Oct 23;28(10):1152-61. Epub 2015 Jun 23.

Department of Transplantation Medicine, Oslo University Hospital, Norway.

Main Problem: Islet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets.

Methods: We determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48 h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR.

Results: Islets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR-signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus.

Conclusion: These findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets.
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http://dx.doi.org/10.1111/tri.12617DOI Listing
October 2015

Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations.

Ther Drug Monit 2015 Oct;37(5):675-80

*Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo; and Departments of †Pharmacology, and ‡Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Everolimus (EVE) is an immunosuppressive drug dosed according to therapeutic drug monitoring in renal transplant recipients. The primary site of action is within activated lymphocytes. EVE is a substrate of the efflux transporter ABCB1 also known as P-glycoprotein. Limited data exist regarding a possible association between whole blood and intralymphocyte concentrations of EVE and the potential influence of ABCB1.

Methods: Twelve renal transplant recipients (5 men and 7 women) treated with EVE underwent a pharmacokinetic investigation where EVE concentrations in whole blood and in peripheral blood mononuclear cells (PBMC) were determined within a dosing interval. In addition, the activity of ABCB1 in PBMC was determined using the Rhodamine123 efflux assay and the patients' genotypes of ABCB1 were determined.

Results: There was a significant correlation between EVE AUC0-12 in whole blood and in PBMC (r = 0.90, P < 0.01), and no association was demonstrated between the ABCB1 activity and EVE PBMC/whole blood ratio of trough concentrations (r = 0.23, P = 0.76). Furthermore, ABCB1 1236C>T, 3435C>T, and 2677G>T/A polymorphism did not influence EVE AUC0-12 PBMC/whole blood ratio.

Conclusions: The results revealed a significant association between EVE whole blood and PBMC concentrations, suggesting that ABCB1-mediated efflux from PBMC to be of minor importance for the distribution of EVE.
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http://dx.doi.org/10.1097/FTD.0000000000000185DOI Listing
October 2015

Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed.

Transplantation 2015 Mar;99(3):528-32

1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 2 Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 3 Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 4 Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years.

Methods: Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio).

Results: Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80).

Conclusion: Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.
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http://dx.doi.org/10.1097/TP.0000000000000384DOI Listing
March 2015

More potent lipid-lowering effect by rosuvastatin compared with fluvastatin in everolimus-treated renal transplant recipients.

Transplantation 2014 Jun;97(12):1266-71

1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 2 Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway. 3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. 4 Department of Pharmacology, Oslo University Hospital, Oslo, Norway. 5 Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI. 6 Center of Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. 7 Department of Nephrology, Drammen Hospital, Drammen, Norway. 8 Address correspondence to: Ida Robertsen, School of Pharmacy, University of Oslo. P. O. Box 1068 Blindern, 0316 Oslo, Norway.

Background: Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed.

Methods: We have aimed to assess the lipid-lowering effect of rosuvastatin as compared with fluvastatin in RTR receiving everolimus. Safety was assessed as the pharmacokinetic (PK) interaction potential of a rosuvastatin/everolimus combination in RTR. A 12-hour everolimus PK investigation was performed in 12 stable RTR receiving everolimus and fluvastatin (80 mg/d). Patients were then switched to rosuvastatin (20 mg/d), and a follow-up 12/24-hour PK investigation of everolimus/rosuvastatin was performed after 1 month. All other drugs were kept unchanged.

Results: In RTR already receiving fluvastatin, switching to rosuvastatin further decreased LDL cholesterol and total cholesterol by 30.2±12.2% (P<0.01) and 18.2±9.6% (P<0.01), respectively. Everolimus AUC0-12 was not affected by concomitant rosuvastatin treatment, 80.3±21.3 μg*h/L before and 78.5±21.9 μg*h/L after, respectively (P=0.61). Mean rosuvastatin AUC0-24 was 157±61.7 ng*h/mL, approximately threefold higher than reported in the literature for nontransplants. There were no adverse events, and none of the patients had or developed proteinuria.

Conclusion: Rosuvastatin showed a superior lipid-lowering effect compared to fluvastatin in stable RTR receiving everolimus. The combination of everolimus/rosuvastatin seems to be as safe as the everolimus/fluvastatin combination.
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http://dx.doi.org/10.1097/01.TP.0000443225.66960.7eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127422PMC
June 2014

Simultaneous quantification of IMPDH activity and purine bases in lymphocytes using LC-MS/MS: assessment of biomarker responses to mycophenolic acid.

Ther Drug Monit 2014 Feb;36(1):108-18

*Department of Medical Biochemistry, Oslo University Hospital; †School of Pharmacy, University of Oslo; and Departments of ‡Anaesthesiology, §Pharmacology, and ¶Transplantation, Oslo University Hospital, Oslo, Norway.

Background: The development of biomarkers describing the individual responses to the immunosuppressant mycophenolic acid (MPA) has focused on the target enzyme activity [inosine 5'-monophosphate dehydrogenase (IMPDH)]. An extended strategy is to quantify the metabolic consequences of IMPDH inhibition. The aim of this study was to develop an assay for quantification of IMPDH activity and related purine bases and to provide preliminary data on the behavior of these biomarkers during clinical exposure to MPA.

Methods: Liquid chromatography-mass spectrometry was used to determine xanthine (IMPDH activity in incubated cell lysate), hypoxanthine, guanine, and adenine derived from free nucleotides in lymphocytes. Analytical performance was assessed, and the biomarkers were examined in CD4⁺ cells from 2 groups: Healthy individuals in a single-dose MPA study (n = 5) and liver transplant recipients on MPA therapy (n = 15).

Results: Coefficients of variation between series were below 10% and 15% for measurement of the purines and IMPDH activity, respectively. Although IMPDH was inhibited, the purine levels increased in response to MPA in 3 of the 5 healthy individuals, and this positive response seemed to be associated with IMPDH1 c.579 + 119 G/G and c.580 - 106 G/G. In the liver transplant study, guanine was not reduced in response to the transient drop in IMPDH activity after MPA dosing. However, there were trends toward decrease in guanine and elevation of hypoxanthine during prolonged MPA therapy. The guanine/hypoxanthine ratio (median) was 37% lower and the adenine level was 21% lower at day 17 compared with day 4 after transplantation.

Conclusions: The assay allows precise quantification of IMPDH activity, hypoxanthine, guanine, and adenine in lymphocytes. Some individuals may possess a counteracting purine response to the MPA-mediated inhibition of IMPDH. Reduction of the guanine/hypoxanthine ratio may be related to prolonged inhibition of IMPDH and seems as an intriguing pharmacodynamic biomarker for MPA.
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http://dx.doi.org/10.1097/FTD.0b013e3182a13900DOI Listing
February 2014

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial.

BMC Res Notes 2012 Aug 7;5:418. Epub 2012 Aug 7.

Department of Pediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway.

Background: This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.

Findings: Five adolescent CFS patients (14-19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.

Conclusion: Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).
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http://dx.doi.org/10.1186/1756-0500-5-418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461473PMC
August 2012

[Drug interactions and immunosuppression in organ transplant recipients].

Tidsskr Nor Laegeforen 2011 Oct;131(20):2000-3

Avdeling for medisinsk biokjemi, Oslo universitetssykehus, Norway.

Background: Immunosuppressive drugs are used to prevent rejection following organ transplantation. Most immunosuppressive drugs have narrow therapeutic concentration ranges. This increases the probability of clinically relevant drug interactions. In the following, we provide an overview of drug interactions that may be of importance to immunosuppressive treatment.

Material And Methods: Data on the interaction of immunosuppressant drugs was obtained by means of a non-systematic literature search in PubMed. Articles were selected on the basis of their clinical relevance.

Results: The literature is primarily concerned with pharmacokinetic interactions. Calcineurin inhibitors (cyclosporine, tacrolimus) and mTOR inhibitors (sirolimus, everolimus) are particularly susceptible to the effects of substances that inhibit or induce cytochrome P450 (CYP) 3A4 and P-glycoprotein. These interactions may lead to the levels of the immunosuppressive drugs in blood altering by a factor of more than 10. Methylprednisolone and prednisolone may also be affected by substances that modulate CYP3A4 and P-glycoprotein. The level of mycophenolate is lowered by simultaneous use of some proton pump inhibitors, antibiotics and anion binders, and by valproic acid and rifampicin. Some immunosuppressive drugs also interact with one another: cyclosporine raises the level of mTOR inhibitors and lowers the level of mycophenolate. In general, the degree of pharmacological interaction will vary from one individual to the next.

Interpretation: In the event of an expected clinically relevant drug interaction, frequent measurements of the concentrations of the drug in question are a good means of achieving individual adjustment of the immunosuppressant treatment. Prior knowledge of drug interactions can thereby contribute to prevent undesirable changes in the immunosuppressant effect.
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http://dx.doi.org/10.4045/tidsskr.11.0138DOI Listing
October 2011

No change in insulin sensitivity in renal transplant recipients converted from standard to once-daily prolonged release tacrolimus.

Nephrol Dial Transplant 2011 Nov 6;26(11):3767-72. Epub 2011 Apr 6.

Department of Nephrology, University of Heidelberg, Heidelberg, Germany.

Background: New-onset diabetes after transplantation may be associated with the use of tacrolimus (Tac) causing impaired insulin release or reduced insulin sensitivity. Such effects have not been studied in renal transplant recipients receiving traditional twice-daily tacrolimus (TacBID) and then compared to the new once-daily prolonged release formulation of tacrolimus (TacOD).

Methods: We performed a prospective crossover study of 20 stable non-diabetic renal transplant recipients. All patients underwent one hyperglycaemic clamp on TacBID (3.8 ± 2.2 mg/day) and a new clamp 4-6 weeks after a 1:1 mg/day switch to TacOD (4.0 ± 2.8 mg/day).

Results: Tac trough concentrations decreased from 6.6 ± 2.9 to 5.4 ± 1.4 μg/mL (P = 0.037) and Tac max from 21.3 ± 8.4 to 15.2 ± 3.5 μg/L (P = 0.001). Tac AUC(0-24) was reduced from 265 ± 112 to 218 ± 47 μg × h/L (P = 0.12). The hyperglycaemic clamp did not detect any change in insulin sensitivity index after conversion [0.26 ± 0.21 versus 0.26 ± 0.25 μmol/min/kg/(pmol/L insulin), P = 0.99] nor any change in first (334 ± 274 versus 353 ± 248 μIU × min/mL, P = 0.41) or second phase insulin secretion (224 ± 155 versus 263 ± 210 μIU × min/mL/mmol glucose, P = 0.60) on TacBID versus TacOD.

Conclusions: Conversion from standard TacBID to TacOD on a 1:1 mg basis is safe. In spite of a reduced Tac exposure, there was no change in insulin release or sensitivity in renal transplant recipients.
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http://dx.doi.org/10.1093/ndt/gfr153DOI Listing
November 2011

Pharmacodynamics of mycophenolic acid in CD4+ cells: a single-dose study of IMPDH and purine nucleotide responses in healthy individuals.

Ther Drug Monit 2008 Dec;30(6):647-55

Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.

Mycophenolate mofetil is used in rejection prophylaxis after allograft transplantation. The highly variable pharmacokinetics and pharmacodynamics (PD) of the active moiety mycophenolic acid (MPA) render this drug attractive for therapeutic monitoring. The aim of this study was to characterize the exposure-response relationship for MPA to guide future strategies for individualized therapy based on PD monitoring. A single-dose (100, 250, 500, and 1000 mg mycophenolate mofetil) crossover exposure-response study of MPA PD in CD4 cells was performed in 5 healthy individuals. The activity of inosine 5'-monophosphate dehydrogenase (IMPDH) at time 0 ranged from 1.2 to 7.2 pmol per 10 cells/min. IMPDH was strongly inhibited by MPA; MPA EC50 (concentration required for 50% inhibition) of 2.3 mg/L was determined by a pooled data analysis. Decreased IMPDH gene expression was associated with the exposure to MPA. There were no immediate reductions of guanine nucleotides. On the contrary, a trend toward increased guanosine triphosphate was observed. IMPDH activity AUC0-12h approached maximum reduction at MPA AUC0-12h 22 mg x h/L (corresponding to the 500 mg dose), whereas plasma concentrations exceeding approximately 6 mg/L did not further increase the IMPDH inhibition. The results suggest that guanine nucleotides in circulating lymphocytes may not serve as immediate response biomarkers to MPA. Strategies for preventing over- or underexposure to MPA may be developed by means of IMPDH activity combined with MPA concentration measurement.
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http://dx.doi.org/10.1097/FTD.0b013e31818955c3DOI Listing
December 2008

Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients.

Nephrol Dial Transplant 2008 Mar 23;23(3):1048-53. Epub 2007 Oct 23.

Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, 0316 Oslo, Norway.

Background: The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and hyperparathyroidism; however, the interaction with calcineurin inhibitors and mycophenolate has not been evaluated.

Methods: In the present study the effects of cinacalcet on the pharmacokinetics of cyclosporine A (CsA), tacrolimus (Tac) and mycophenolate were investigated in 14 renal transplant recipients with stable renal function (mean creatinine 126.4 +/- 45.3 micromol/L). The patients were treated with either CsA (n = 8) or Tac (n = 6) in combination with mycophenolate/azathioprine and steroids. Twelve-hour pharmacokinetic investigations to measure CsA and its six main metabolites, Tac and mycophenolate concentrations were performed before and after 1-week treatment with 30 mg cinacalcet once daily.

Results: Cinacalcet treatment induced a significant 14.3 +/- 12.1% decrease in Tac AUC(0-12) (P = 0.039). Tac C(max), T(max) and T(1/2) also tended to decrease. The pharmacokinetics of CsA and mycophenolate were not significantly affected by concomitant treatment with cinacalcet. However, the secondary CsA metabolite, AM19, showed a significant increase of 9.0 +/- 9.5% during cinacalcet treatment (P = 0.040). Renal function decreased significantly from 78 +/- 11 to 72 +/- 12 mL/min (P = 0.019) and correlated with the increased levels of metabolite AM19 in the CsA group. Renal function was unchanged in the Tac group.

Conclusion: Cinacalcet treatment showed a moderate effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. This interaction appears to have minor clinical relevance. However, it is advisable to monitor renal function in CsA-treated patients due to the observed decrease in renal function.
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http://dx.doi.org/10.1093/ndt/gfm632DOI Listing
March 2008

Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy.

Ther Drug Monit 2006 Oct;28(5):608-13

Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an established target in immunosuppression following organ transplantation. In lymphocytes, reversible inhibition of this enzyme by mycophenolic acid (MPA) results in reduced production of guanine and deoxyguanine nucleotides and thereby retarded proliferation of activated cells. In order to examine MPA pharmacodynamics in renal allograft recipients, the authors have developed an assay for the determination of IMPDH activity in CD4+ cells directly isolated from a small blood volume. Paramagnetic beads coated with anti-CD4 antibodies were utilized for the cell isolation. The intracellular MPA concentration was restored by incubating the cells in microfiltrated plasma from the original sample. Inosine 5'-monophosphate (IMP; substrate) and nicotine adenine dinucleotide (NAD; co-factor) were added to cell lysates, and IMPDH activity was quantified as the xanthosine 5'-monophosphate (XMP) production rate (pmol/10 cells/min) determined by liquid chromatography after hydrolytic cleavage to xanthine. The reaction kinetics were saturated with IMP and NAD concentrations of 1.79 micromol/L and 0.38 micromol/L, respectively. The production rate was linear in the interval 0.13 to 8.7 pmol XMP/min. Total interseries CVs based on seven replicates at each MPA concentration 0, 2.2, and 8.6 microg/mL were 25%, 16%, and 13%, respectively. When a single 1 gram mycophenolate mofetil dose was administered to a healthy individual, the measured IMPDH activity was 13% of predose value at the MPA peak concentration. The present assay allows reliable determination of IMPDH activity in CD4+ cells during MPA exposure, reducing the potential influence of sample preparation on the measured enzyme activity to a minimum. The assay may be applied to assess MPA pharmacodynamics during immunosuppressive treatment, maintaining the influence of intracellular MPA on the IMPDH activity.
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http://dx.doi.org/10.1097/01.ftd.0000245680.38143.caDOI Listing
October 2006
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