Drug-related problems and satisfaction among patients receiving pharmacist-led consultations at the initiation of cardiovascular drugs.

Background: Drug-related problems (DRPs) lead to substantial morbidity and mortality and increase healthcare costs. Several interventions have been developed to reduce DRPs and improve the outcome of drug therapy.

Objective: To investigate DRPs identified through a pharmacist-led intervention and to assess patient satisfaction with the intervention.

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

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).

Effect of a pharmacist-led intervention on adherence among patients with a first-time prescription for a cardiovascular medicine: a randomized controlled trial in Norwegian pharmacies.

Objective: To examine whether a pharmacist-led intervention improves medication adherence among patients who have filled a first-time prescription for a cardiovascular medicine.

Methods: Design: Unblinded randomized controlled trial.

Setting: 67 Norwegian pharmacies, October 2014-June 2015.

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

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.

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

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.

NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation.

Aims: Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy.

Methods: In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.

Is toxicity of PMMA (paramethoxymethamphetamine) associated with cytochrome P450 pharmacogenetics?

In 2010-2013, 29 fatal intoxications related to the designer drug paramethoxymethamphetamine (PMMA, 4-methoxymethamphetamine) occurred in Norway. The current knowledge about metabolism and toxicity of PMMA in humans is limited. Metabolism by the polymorphic cytochrome P450 (CYP) 2D6 enzyme to the psychoactive metabolite 4-hydroxymethamphetamine (OH-MA), and possibly by additional enzymes, is suggested to be involved in its toxicity.

Drug target molecules to guide immunosuppression.

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.

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

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.

Improved Tacrolimus Target Concentration Achievement Using Computerized Dosing in Renal Transplant Recipients--A Prospective, Randomized Study.

Background: Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus concentrations within the target range. Computerized dose individualization using population pharmacokinetic models may be helpful. The objective of this study was to prospectively evaluate the target concentration achievement of tacrolimus using computerized dosing compared with conventional dosing performed by experienced transplant physicians.

Glutathione Transferase Gene Variants Influence Busulfan Pharmacokinetics and Outcome After Myeloablative Conditioning.

Background: Busulfan (Bu) and cyclophosphamide (Cy) are frequently included in conditioning regimens before hematopoietic stem cell transplantation (HSCT). Both drugs are detoxified by glutathione transferases (GST), and GST gene variants may explain some of the interindividual variability in pharmacokinetics and drug toxicity.

Methods: The study investigated adult patients (n = 114) receiving oral Bu pre-HSCT.

Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling.

Aims: The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models.

Methods: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting.

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

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 influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients.

Purpose: Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism.

Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation.

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C(0) concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking.

Tacrolimus exposure and mycophenolate pharmacokinetics and pharmacodynamics early after liver transplantation.

Background: Mycophenolic acid (MPA) and tacrolimus play important roles in immunosuppressive therapy after solid organ transplantation (Tx) and show large intra- and interindividual pharmacokinetic (PK) variabilities. The purpose of this study was to describe the intra- and interindividual variabilities of MPA and tacrolimus PKs during the first 3 weeks after adult liver transplantation. Furthermore, inosine monophosphate dehydrogenase activity was investigated.

Importance of hematocrit for a tacrolimus target concentration strategy.

Purpose: To identify patient characteristics that influence tacrolimus individual dose requirement in kidney transplant recipients.

Methods: Data on forty-four 12-h pharmacokinetic profiles from 29 patients and trough concentrations in 44 patients measured during the first 70 days after transplantation (1,546 tacrolimus whole blood concentrations) were analyzed. Population pharmacokinetic modeling was performed using NONMEM 7.

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

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.

A taste of individualized medicine: physicians' reactions to automated genetic interpretations.

The potential of pharmacogenomics is well documented, and functionality exploiting this knowledge is about to be introduced into electronic medical records. To explore physicians' reactions to automatic interpretations of genetic tests, we built a prototype with a simple interpretive algorithm. The algorithm was adapted to the needs of physicians handling immunosuppressive treatment during organ transplantation.

A novel mucopolysaccharidosis type I associated splice site mutation and IDUA splice variants.

Mucopolysaccharidosis type I is an autosomal recessive disorder caused by deficiency of α-l-iduronidase, encoded by the IDUA gene. More than 100 disease causing mutations have been reported in the gene, resulting in a wide range of phenotypes. Here we describe a previously unreported IDUA splice site mutation (NG_008103.

Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.

Background: Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA).

Reduced elimination of cyclosporine A in elderly (>65 years) kidney transplant recipients.

Background: Physiologic functions that may affect pharmacokinetics of drugs are altered in elderly patients. The current study was performed to elucidate the effect of age on cyclosporine A (CsA) pharmacokinetics in renal transplant recipients.

Method: Twenty-five renal transplant recipients on CsA treatment were included in the study.

Expression of IMPDH1 is regulated in response to mycophenolate concentration.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes de novo guanine nucleotide synthesis. Mycophenolic acid (MPA) exerts immunosuppressive effects by inhibiting IMPDH. The aim of this study was to investigate gene expressions of two IMPDH isoforms, during in vivo exposure to MPA.

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

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.

Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients.

Background: We investigated cyclosporine A (CsA) concentrations at the site of action, inside T-lymphocytes, to evaluate its applicability as a new supplementary therapeutic drug monitoring method after renal transplantation.

Method: In this prospective single-center study, 20 kidney transplant recipients, mean age 54 (range 21-74) years, on CsA-based immunosuppression were included within 2 weeks posttransplant and followed for 3 months. Nine patients also had one full 12-hour pharmacokinetic profile performed.