Publications by authors named "Ida Robertsen"

27 Publications

  • Page 1 of 1

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

Transpl Int 2021 May 15. Epub 2021 May 15.

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
May 2021

Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes.

J Pharm Sci 2021 01 19;110(1):432-437. Epub 2020 Oct 19.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. Electronic address:

Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CL) values for CYP3A correlated negatively with body weight (r = -0.43, p < 0.01), waist circumference (r = -0.47, p < 0.01), hip circumference (r = -0.51, p < 0.01), fat percent (r = -0.41, p < 0.05), fat mass (r = -0.48, p < 0.01) and BMI (r = -0.46, p < 0.01). Linear regression analysis showed that CL values for CYP3A decreased with 5% with each 10% increase in body weight (r = 0.12, β = -0.558, p < 0.05). There were no correlations between body weight measures and CL values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.
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http://dx.doi.org/10.1016/j.xphs.2020.10.027DOI Listing
January 2021

Severe Mycophenolate Intoxication in a Solid Organ Transplant Recipient-No Intervention Actually Needed.

Transplant Direct 2020 Oct 25;6(10):e609. Epub 2020 Sep 25.

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

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http://dx.doi.org/10.1097/TXD.0000000000001058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523787PMC
October 2020

Proteomics-Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight.

Clin Pharmacol Ther 2021 Mar 18;109(3):762-771. Epub 2020 Oct 18.

Department of Pharmacy and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time-concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293-transfected cells, and developed a semimechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measured in vivo plasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two-fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (C ; 76%; AFE: 1.05), and terminal half-life (t ; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T
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http://dx.doi.org/10.1002/cpt.2056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984432PMC
March 2021

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

Measuring Intracellular Concentrations of Calcineurin Inhibitors: Expert Consensus from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Expert Panel.

Ther Drug Monit 2020 10;42(5):665-670

Clinical Chemistry Department, Cliniques Universitaires St Luc, Université catholique de Louvain, LTAP, Brussels, Belgium.

Background: Therapeutic drug monitoring (TDM) of the 2 calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporin A, has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection (AR) rates and treatment-related toxicities have been reduced. Irrespective, AR and toxicity still occur in patients who have undergone transplantation, showing blood CNI concentrations within the therapeutic range. Moreover, the AR rate is no longer decreasing. Hence, smarter TDM approaches are necessary. Because CNIs exert their action inside T lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. The intracellular CNI concentration may be more directly related to the drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the preanalytical and analytical stages, and standardization seems essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations.

Methods: Under the auspices of the International Association of TDM and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented preanalytical and analytical recommendations for measuring intracellular CNI concentrations.
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http://dx.doi.org/10.1097/FTD.0000000000000780DOI Listing
October 2020

Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End-Stage Renal Disease.

Clin Pharmacol Ther 2020 10 1;108(4):866-873. Epub 2020 Jun 1.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.

Drug dosing is challenging in patients with end-stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P-glycoprotein (P-gp)/organic anion-transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (-3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P-gp/OATP activity.
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http://dx.doi.org/10.1002/cpt.1875DOI Listing
October 2020

Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance.

Kidney Int Rep 2020 Feb 6;5(2):189-198. Epub 2019 Dec 6.

Department of Pharmacy, University of Oslo, Oslo, Norway.

Introduction: There is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min.

Methods: A nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min.

Results: The clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %.

Conclusion: Using an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min.
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http://dx.doi.org/10.1016/j.ekir.2019.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000849PMC
February 2020

Generic drugs – not as equivalent as we think?

Tidsskr Nor Laegeforen 2019 Dec 9;139(18). Epub 2019 Dec 9.

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http://dx.doi.org/10.4045/tidsskr.19.0740DOI Listing
December 2019

Reply to letter: "What about drug bioavailability in patients who had bariatric surgery and dependent on immunosuppressives?"

Obes Rev 2020 02 20;21(2):e12954. Epub 2019 Nov 20.

Morbid Obesity Centre, Department of Medicine, Vestfold Hospital Trust, Tønsberg, Norway.

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http://dx.doi.org/10.1111/obr.12954DOI Listing
February 2020

A Comparative Analysis of Cytochrome P450 Activities in Paired Liver and Small Intestinal Samples from Patients with Obesity.

Drug Metab Dispos 2020 01 4;48(1):8-17. Epub 2019 Nov 4.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway (V.K., I.R., A.Å., H.C.); Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (V.K., A.Å.); Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (A.P., C.W., S.A., T.B.A.); Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (M.K.K.); Department of Health Sciences, OsloMet-Oslo Metropolitan University, Oslo, Norway (M.K.K.); Department of Pharmacy, Uppsala University, Uppsala, Sweden (C.W., P.A.); The Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A., J.H.); Department of Surgery, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A.); Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (J.H.); Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (C.K.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); and Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden (T.B.A.).

The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated ( = 0.74, < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A ( > 0.05). Small intestinal CYP3A activities were higher in females compared with males ( < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index ( = -0.72, < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population.
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http://dx.doi.org/10.1124/dmd.119.087940DOI Listing
January 2020

Tacrolimus Area Under the Concentration Versus Time Curve Monitoring, Using Home-Based Volumetric Absorptive Capillary Microsampling.

Ther Drug Monit 2020 06;42(3):407-414

Department of Transplantation Medicine, Oslo University Hospital.

Background: Therapeutic drug monitoring (TDM) of tacrolimus (Tac) is mandatory in renal transplant recipients (RTxR). Area under the concentration versus time curve (AUC) is the preferred measure for Tac exposure; however, for practical purposes, most centers use trough concentrations as a clinical surrogate. Limited sampling strategies in combination with population pharmacokinetic model-derived Bayesian estimators (popPK-BE) may accurately predict individual AUC. The use of self-collected capillary microsamples could simplify this strategy. This study aimed to investigate the potential of AUC-targeted Tac TDM using capillary microsamples in combination with popPK-BE.

Methods: A single-center prospective pharmacokinetic study was conducted in standard-risk RTxR (n = 27) receiving Tac twice daily. Both venous and capillary microsamples (Mitra; Neoteryx, Torrance, CA) were obtained across 2 separate 12-hour Tac dosing intervals (n = 13 samples/AUC). Using popPK-BE, reference AUC (AUCref) was determined for each patient using all venous samples. Different limited sampling strategies were tested for AUC predictions: (1) the empiric sampling scheme; 0, 1, and 3 hours after dose and (2) 3 sampling times determined by the multiple model optimal sampling time function in Pmetrics. Agreement between the predicted AUCs and AUCref were evaluated using C-statistics. Accepted agreement was defined as a total deviation index ≤±15%.

Results: The AUC from capillary microsamples revealed high accuracy and precision compared with venous AUCref, and 85% of the AUCs had an error within ±11.9%. Applying microsamples at 0, 1, and 3 hours after dose predicted venous AUCref with acceptable agreement. Patients performed self-sampling with acceptable accuracy.

Conclusions: Capillary microsampling is patient-centered, making AUC-targeted TDM of Tac feasible without extended hospital stays. Samples obtained 0, 1, and 3 hours after dose, combined with popPK-BE, accurately predict venous Tac AUC.
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http://dx.doi.org/10.1097/FTD.0000000000000697DOI Listing
June 2020

The influence of bariatric surgery on oral drug bioavailability in patients with obesity: A systematic review.

Obes Rev 2019 09 24;20(9):1299-1311. Epub 2019 Jun 24.

Morbid Obesity Centre, Department of Medicine, Vestfold Hospital Trust, Tønsberg, Norway.

Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before-after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux-en-Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long-term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss.
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http://dx.doi.org/10.1111/obr.12869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852510PMC
September 2019

Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus-treated transplant recipients?

Br J Clin Pharmacol 2020 12 29;86(12):2535. Epub 2019 May 29.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.

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http://dx.doi.org/10.1111/bcp.13984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688523PMC
December 2020

Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus.

Diabetes Care 2019 06 12;42(6):1067-1074. Epub 2019 Mar 12.

Section of Nephrology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have lately become the recommended treatment in patients with type 2 diabetes and high cardiovascular risk. Patients with posttransplant diabetes mellitus (PTDM) also have high cardiovascular risk. The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with PTDM.

Research Design And Methods: Forty-nine renal transplant recipients were included in an investigator-initiated, single-center, prospective, double-blind study and randomized to receive either 10 mg empagliflozin or placebo once daily for 24 weeks. Patients transplanted >1 year ago, diagnosed with PTDM, with stable renal function (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m), and with stable immunosuppressive therapy were studied.

Results: Forty-four renal transplant recipients (22 empagliflozin/22 placebo, 34 males) completed the study. Median (interquartile range) change in glycated hemoglobin (HbA) was significantly reduced with empagliflozin compared with placebo: -0.2% (-0.6, -0.1) (-2.0 mmol/mol [-6.5, -1.0]) vs. 0.1% (-0.1, 0.4) (1.0 mmol/mol [-0.75, 3.8]) ( = 0.025). The magnitude of glucose reduction was dependent on GFR and baseline HbA. The treatment also resulted in a significant reduction in body weight of -2.5 kg (-4.0, -0.05) compared with an increase of 1.0 kg (0.0, 2.0) in the placebo group ( = 0.014). There were no significant differences between the groups in adverse events, immunosuppressive drug levels, or eGFR.

Conclusions: Empagliflozin appeared safe and improved glycemic control in renal transplant recipients with PTDM compared with placebo. A concomitant reduction in body weight was seen.
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http://dx.doi.org/10.2337/dc19-0093DOI Listing
June 2019

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study.

Transpl Int 2019 03 15;32(3):257-269. Epub 2018 Oct 15.

School of Pharmacy, University of Oslo, Oslo, Norway.

Patients with high tacrolimus clearance are more likely to experience transient under-immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1-year post-transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1-year post-transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11-2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18-3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.
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http://dx.doi.org/10.1111/tri.13356DOI Listing
March 2019

Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL).

BMJ Open 2018 05 29;8(5):e021878. Epub 2018 May 29.

Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden.

Introduction: Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups.

Methods And Analysis: This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUC/AUC) of midazolam (CYP3A4 probe), systemic exposure (AUC) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers.

Ethics And Dissemination: The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants.

Trial Registration Number: NCT02386917.
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http://dx.doi.org/10.1136/bmjopen-2018-021878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988193PMC
May 2018

Determination of Tacrolimus Concentration and Protein Expression of P-Glycoprotein in Single Human Renal Core Biopsies.

Ther Drug Monit 2018 06;40(3):292-300

Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo.

Background: Tacrolimus (TAC) is currently the cornerstone of immunosuppressive protocols for renal transplant recipients. Despite therapeutic whole blood monitoring, TAC is associated with nephrotoxicity, and it has been hypothesized that intrarenal accumulation of TAC and/or its metabolites are involved. As TAC is a substrate of P-glycoprotein (P-gp), the expression and activity of this efflux transporter could influence the levels of TAC in renal tissue. The primary aim of this study was to develop and validate a method for quantification of TAC in tissue homogenates from single human renal core biopsies. The secondary aim was to provide measures of P-gp expression and of the demethylated metabolites of TAC in the same renal biopsy.

Methods: Human renal tissue, with and without clinical TAC exposure, was used for method development and validation. Homogenates were prepared with bead-beating, and concentrations of TAC and its demethylated metabolites were analyzed with liquid chromatography tandem mass spectrometry after protein precipitation. A Western blot method was used for semiquantification of P-gp expression in the homogenates. The final methods were applied to renal core biopsies from 2 transplant patients.

Results: The TAC assay showed within- and between-run mean accuracy between 99.7% and 107% and coefficients of variation ≤6.7%. Matrix effects were nonsignificant, and samples were stable for 3 months preanalytically when stored at -80°C. TAC concentrations in the renal core biopsies were 62.6 and 43.7 pg/mg tissue. The methods for measurement of desmethyl-TAC and P-gp expression were suitable for semiquantification in homogenates from renal core biopsies.

Conclusions: These methods may be valuable for the elucidation of the pharmacokinetic mechanisms behind TAC-induced nephrotoxicity in renal transplant recipients.
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http://dx.doi.org/10.1097/FTD.0000000000000510DOI Listing
June 2018

A Limited Sampling Strategy to Estimate Exposure of Everolimus in Whole Blood and Peripheral Blood Mononuclear Cells in Renal Transplant Recipients Using Population Pharmacokinetic Modeling and Bayesian Estimators.

Clin Pharmacokinet 2018 11;57(11):1459-1469

Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France.

Background And Objective: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients.

Methods: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set.

Results: A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 haplotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration-time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively).

Conclusion: The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials.
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http://dx.doi.org/10.1007/s40262-018-0646-5DOI Listing
November 2018

How to Report and Interpret Bioequivalence Data in Solid Organ Transplant Recipients.

Transplantation 2017 11;101(11):e347

1 Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway. 2 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.

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http://dx.doi.org/10.1097/TP.0000000000001894DOI Listing
November 2017

High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation.

Transplantation 2017 08;101(8):e273-e279

1 School of Pharmacy, University of Oslo, Oslo, Norway. 2 Western Norway University of Applied Sciences, Norway. 3 Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4 Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 5 Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Background: Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes.

Methods: A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [μg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated.

Results: In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not.

Conclusions: High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001796DOI Listing
August 2017

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

Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients.

Transplant Res 2013 Apr 8;2(1). Epub 2013 Apr 8.

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

Background: In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients.

Methods: Ten heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann-Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used.

Results: Three patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/106 cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11).

Conclusions: The study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients.
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http://dx.doi.org/10.1186/2047-1440-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643826PMC
April 2013

Rimonabant affects cyclosporine a, but not tacrolimus pharmacokinetics in renal transplant recipients.

Transplantation 2009 Apr;87(8):1221-4

Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.

Background: Obesity is a common problem following renal transplantation. Rimonabant, a cannabinoid-1 receptor blocker, offers a new approach for reducing obesity.

Methods: The potential pharmacokinetic interaction between rimonabant and cyclosporine A (CsA, n=10) and tacrolimus (Tac, n=8) was assessed in stable renal transplant recipients 6.2 (0.9-21.7) years posttransplant. A 12-hour pharmacokinetic profile was obtained before and after two months of concomitant treatment with 20 mg rimonabant each morning.

Results: Rimonabant treatment induced a moderate, but significant increase in CsA AUC0-12 (19.8+/-16.1 %, P=0.005). Cmax and C2 values tended to increase whereas C0 remained unaffected. Tac pharmacokinetics was not significantly affected by rimonabant treatment. Eleven of 18 patients experienced adverse events. Two patients reported depressions and one reported severe nightmares.

Conclusions: The effect on CsA pharmacokinetics is probably of marginal clinical relevance since trough concentrations were unaltered, but CsA concentrations should probably be more closely monitored if rimonabant treatment is initiated, preferably by C2 monitoring.
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http://dx.doi.org/10.1097/TP.0b013e31819f1001DOI Listing
April 2009