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

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/10(6) 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

Rimonabants effekter på farmakokinetikken til ciklosporin A og takrolimus i nyretransplanterte pasienter

Bakgrunn: De siste årene har overvekt og fedme blitt et økende problem hos nyretransplanterte pasienter, og bidrar til en økt risiko for kardiovaskulær sykdom. Kardiovaskulær sykdom er allerede den vanligste dødsårsaken hos nyretransplanterte, og det er derfor et stort behov for å minimere risikofaktorer for kardiovaskulær morbiditet og mortalitet hos denne pasientpopulasjonen. Nyretransplanterte blir behandlet med en livslang immunsuppresjonterapi, der kalsineurinhemmerene CsA og Tac, utgjør grunnsteinene. Begge legemidlene er karakterisert av et smalt terapeutisk vindu. Det er derfor svært viktig at alle nye legemidler vurderes som å ha et potensial til å påvirke CsA eller Tac konsentrasjoner inntil data eller erfaring tilsier det motsatte. Rimonabant er et nytt legemiddel, som i tillegg til sine vektreduserende egenskaper, også har vist gunstige effekter på andre risikofaktorer for kardiovaskulær sykdom av interesse for nyretransplanterte pasienter. En interaksjonsstudie mellom kalsineurinhemmerene og rimonabant har ikke tidligere blitt utført. Mål og metoder: I denne studien ble effektene av rimonabant på farmakokinetikken til CsA og Tac undersøkt i 18 pasienter med stabil nyrefunksjon. Pasientene brukte enten CsA (n = 10) eller Tac (n = 8), i tillegg til steroider og mykofenolat. 12-timers farmakokinetikk undersøkelser for å måle CsA og Tac konsentrasjoner ble utført før og etter en to måneders lang behandlingsperiode med 20 mg rimonabant daglig. Det ble i tillegg utført en oral glukosebelastning både før og etter rimonabantbehandlingen for å undersøke om pasientenes insulinsensitivitet ble forbedret av rimonabant. Det ble også observert om rimonabantbehandlingen førte til en reduksjon av kroppsvekten til pasientene. Resultater: En to måneders lang behandlingsperiode med rimonabant induserte en moderat 23 ± 56 %, men signifikant økning i CsA AUC0-12 (p = 0,043) etter at seks av pasientene var analysert. Farmakokinetikken til Tac endret seg ikke i noen relevant grad og nyrefunksjonen til pasientene holdt seg stabil under rimonabantbehandlingen. Det ble i tillegg vist en signifikant nedgang i vekt/BMI etter behandling med rimonabant. Insulinsensitiviteten viste derimot ingen forbedring etter den to måneders lange rimonabantbehandlingen. Konklusjon: En samtidig administrering av rimonabant i to måneder viste en moderat effekt på farmakokinetikken til CsA. Dette er av et omfang som det må ta hensyn til i klinikken, sett at analysene av de tre siste pasientene viser den samme tendensen. Farmakokinetikken til Tac ble ikke påvirket i noen relevant grad, og dette indikerer at det vil være trygt å administrere rimonabant samtidig med Tac i nyretransplanterte pasienter. Rimonabant induserte en svak nedgang i vekt/BMI, men hadde ingen effekt på insulinsensitiviteten etter den to måneders lange behandlingsperioden

Pharmacological treatments and monitoring strategies to improve outcome in solid organ transplants

Following solid organ transplantation individualizing the immunosuppressive therapy to obtain an optimal balance between therapeutic efficacy and the occurrence of adverse events is the ultimately goal. This is complicated by the high intra- and interindividual pharmacokinetic variability and the narrow therapeutic index of the immunosuppressive drugs. Small variations in drug exposure may result in suboptimal immunosuppression or drug toxicity, with potentially adverse effects on patient outcomes. Therapeutic drug monitoring (TDM) is therefore mandatory in order to individualize the therapy. More knowledge and further improvements of drug treatment strategies and monitoring techniques are still desirable to further improve TDM and hence potentially both short- and long term outcomes after transplantation. The primary objective of this thesis was to investigate some different pharmacological treatments and monitoring strategies to improve outcome in solid organ transplants. In this thesis results from three prospective clinical trials in solid organ transplants are presented. The lipid-lowering effect of rosuvastatin in comparison with fluvastatin, and the potential bilateral drug-drug interaction between rosuvastatin and everolimus (EVE) were assessed in renal transplant recipients at a stable phase following transplantation. Further, the relationship between both cyclosporine A (CsA) and EVE concentrations in different body compartments were evaluated as potential TDM tools in heart- and renal transplant recipients, respectively. Finally, the bioequivalence of an approved generic tacrolimus (TAC) was investigated with the original drug as reference in elderly stable renal transplant recipients. In renal transplant recipients receiving EVE based immunosuppression and treated with fluvastatin, a switch to rosuvastatin induced a significant additional lipid lowering effect. The combination of EVE and rosuvastatin appears to be safe as EVE pharmacokinetics were unaffected following the switch to rosuvastatin. The systemic exposure of rosuvastatin was less than 3-fold higher compared to non-transplants reported in the literature when combined with EVE, and this is comparable to what is previously shown for fluvastatin in combination with CsA, a combination considered to be safe in renal transplant recipients. Safely achieving reduction in lipids could be of great importance in reducing cardiovascular risk in this high risk population. No correlation between CsA concentrations in whole blood, T-lymphocytes or endomyocardial tissue was established in heart transplant recipients, potentially challenging traditional TDM based on whole blood CsA concentrations in these patients. In contrast, EVE concentrations in whole blood and PBMC correlated well and supports that TDM of EVE in whole blood is an appropriate choice. The generic TAC formulation was not found to be bioequivalent to the original drug in elderly renal transplant recipients. Use of generic TAC resulted in a significantly higher systemic drug exposure. In the long run this may put the patients at higher risk of calcineurin inhibitor-related toxicity and impaired long-term outcomes. Importantly, the lack of bioequivalence would not have been detected by the standard monitoring parameter, TAC trough concentrations, as these concentrations were similar for both formulations Generic TAC should be used with caution in elderly renal transplant recipients and it should be recognized that bioequivalence studies performed in healthy volunteers do not necessarily reflect the average transplant recipient

Barns opplevelse av konvensjonell røntgen og tiltak for optimalisering

Problemstilling: Hvordan opplever pediatriske pasienter konvensjonelle røntgenundersøkelser og hvilke tiltak kan iverksettes for å gjøre deres opplevelse optimal? Hensikt: Hensikten med denne oppgaven er å forske på barns opplevelse av konvensjonell røntgen og dermed finne tiltak som kan gjøre deres opplevelse optimal. Metode: Oppgaven bygger på en kvalitativ metode i form av et litteraturstudie. Det er benyttet fem vitenskapelige artikler som omhandler barns opplevelse av konvensjonell røntgen og ulike tiltak som kan benyttes for å gjøre undersøkelsen optimal. Resultat: Denne studien viser at de fleste barn har positive emosjonelle opplevelser ved konvensjonell røntgen, men det er også enkelte tilfeller hvor barn opplever en røntgenundersøkelse som negativt. Resultatene viser at ulike tiltak som kan optimalisere deres opplevelse av en røntgenundersøkelse, er blant annet hvordan radiografen interagerer med barnet, miljødistraksjoner og foreldrenes tilstedeværelse. Konklusjon: Barnets opplevelse av en røntgenundersøkelse vil variere siden barn er ulike individer i ulike utviklingsstadier. Valg av tiltak og deres effektivitet vil variere ut ifra barnas alder, men når dette er sagt ser vi at tiltakene har god effekt når de blir benyttet

A Method for Evaluating Robustness of Limited Sampling Strategies—Exemplified by Serum Iohexol Clearance for Determination of Measured Glomerular Filtration Rate

In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitoring. However, it is not uncommon for the actual sample time to deviate from the optimal one. In this work, we evaluate the robustness of parameter estimations to such deviations in an LSS. A previously developed 4-point LSS for estimation of serum iohexol clearance (i.e., dose/AUC) was used to exemplify the effect of sample time deviations. Two parallel strategies were used: (a) shifting the exact sampling time by an empirical amount of time for each of the four individual sample points, and (b) introducing a random error across all sample points. The investigated iohexol LSS appeared robust to deviations from optimal sample times, both across individual and multiple sample points. The proportion of individuals with a relative error greater than 15% (P15) was 5.3% in the reference run with optimally timed sampling, which increased to a maximum of 8.3% following the introduction of random error in sample time across all four time points. We propose to apply the present method for the validation of LSS developed for clinical use

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

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

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

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\u3c0.01) and 18.2±9.6% (P\u3c0.01), 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. © 2014 by Lippincott Williams & Wilkins

Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance

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 m2 (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