Search

In vitro evidence show that the acyl- β -D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 µM. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl- β -D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared to placebo, with ratios of geometric means of 1.02 [ P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 ( P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl- β -D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase ( P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl- β -D-glucuronide were very low compared to its CYP2C8 inhibition constant (ratio << 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. Significance Statement The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of CYP2C8. Even though candesartan acyl- β -D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations.

Aims: The British Pharmacological Society and UK Medical Schools Council Prescription Safety Assessment (BPS/MSC PSA) is an electronic platform developed for assessing the prescription skills of medical students. Our aim was to investigate the feasibility of the BPS/MSC PSA in addressing prescribing competencies among junior doctors in a hospital setting., Methods: The Department of Clinical Pharmacology at Odense University Hospital established a Danish translated programme using the BPS/MSC PSA platform. We launched a formal 3-year programme in 2021, potentially assessing all first-year doctors at Odense University Hospital and Esbjerg Regional Hospital. Participation was followed by a survey., Results: During the period of 2021 to 2023 n = 364 doctors were invited, from which n = 246 participated. The compliance rate increased from 38% in 2021 to 88% in 2023. The mean assessment score (points normalized to percentage) across n = 246 participants was 71%, and 94% achieved a score of at least 50%. A subset of participants responded to the survey, with the majority of those completing the questionnaire indicating that the purpose of the assessment was clear. The items related to difficulty and number of questions received comparable evaluations, and most respondents found the questions clinically relevant., Conclusion: It is feasible to translate and implement the BPS/MSC PSA in a Danish hospital setting. The programme provides insight into the prescribing competencies of junior doctors and the participants are generally positive., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model., Methods: We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM., Results: Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (R C:PBMC ), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher R C:PBMC ratios of 42.4% and 60.7%, respectively., Conclusion: Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Clonidine is an α-adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction in sympathetic outflow and release of certain neurotransmitters. Clonidine has multiple uses across various medical conditions. One of its uses is as adjuvant to anaesthetic and analgesic agents specially opioids, mostly administered through intravenous and epidural routes. The opioids, effective in cancer pain management, are associated with various side effects such as sedation, pruritus, constipation, nausea, respiratory depression, tolerance and dependence. Combination of clonidine with opioids seems to help to achieve better pain management and less need of opioids. Use of clonidine in palliative care has been less common, but it is gradually gaining recognition for its potential benefits in managing symptoms like cancer pain and agitation. This combination approach has been explored in palliative care settings, including cancer pain and agitation, where patients experience complex and refractory symptoms. It seems to be well tolerated and gives better symptom relief. The available literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated. Therefore, the optimal dosing, safety profile and overall effectiveness of subcutaneous clonidine requires further exploration through prospective research studies., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Abstract: Paclitaxel-induced peripheral neuropathy (PIPN) is a barrier to effective cancer treatment and impacts quality of life among patients with cancer. We used a translational approach to assess the utility of neurofilament light chain (NFL) as a biomarker of PIPN in a human cell model and in patients with ovarian cancer. We measured NFL in medium from human induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) exposed to paclitaxel. Serum NFL (sNFL) levels were quantified in 190 patients with ovarian cancer receiving paclitaxel/carboplatin chemotherapy at baseline and after each of the following 2 or 6 cycles. Adverse outcomes related to PIPN were retrospectively obtained, and Cox regression model was performed with different sNFL cut-offs after first cycle. The apparent elimination half-life of sNFL was estimated in patients who discontinued paclitaxel. Paclitaxel neurotoxicity in iPSC-SNs was accompanied by NFL release in a concentration-dependent manner ( P < 0.001, analysis of variance). Serum NFL levels increased substantially in patients during paclitaxel/carboplatin chemotherapy with considerable interindividual variability. Patients with sNFL >150 pg/mL after first cycle had increased risk to discontinue paclitaxel early (unadjusted HR: 2.47 [95% CI 1.16-5.22], adjusted HR: 2.25 [95% CI: 0.88-5.79]). Similar trends were shown for risk of severe PIPN and paclitaxel dose reduction because of PIPN. The median elimination half-life of sNFL was 43 days (IQR 27-82 days). Neurofilament light chain constitutes an objective biomarker of neurotoxicity in iPSC-SNs and in ovarian cancer patients with high sNFL predicting PIPN-related adverse outcomes. If prospectively validated, NFL can be used to study PIPN and may guide clinical decision making and personalize treatment with paclitaxel., (Copyright © 2023 International Association for the Study of Pain.)

Intrauterine hormonal contraception devices are widely used among Danish women. Cases of breast cancer have been reported in women using the devices and studies have found evidence of an increased risk, but a new meta-analysis did not find an increased risk. The reported relative risks in some of the studies are numerically substantial as quoted in this review, but it is very important that physicians take absolute numbers into account when interpreting risk in order to provide the best guidance of patients with regard to contraception and associated risks.

Background: In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping., Patients and Methods: Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank., Results: The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%)., Conclusions: We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity., Objectives: The objective of this study is to present the current evidence for DPD testing in routine oncological practice., Methods: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk., Findings: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively., Conclusions: The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (-0.7-2.4), -5.9 (-11.8 to -0.03) and -1.1 (-2.5-0.4) h/L*10 -6 , respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC M3G/Dose )/(AUC morphine/Dose ) and (AUC M6G/Dose )/(AUC morphine/Dose ) ratio was reduced, -1.8 (-3.2 to -0.4) and -0.4 (-0.7 to -0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: The risk of drug-drug cross contamination in drug dispensing robots in hospital pharmacies causes cumbersome restraints to be put on the production of the robot for example by scheduling high-risk drugs to be dispensed at the end of the day. However, we were unable to find published data on the matter, and therefore performed a worst-case scenario study to assess the magnitude of the problem., Methods: We measured dexamethasone residue left on the suction cup after the production of 100 and 400 dexamethasone tablets, and after 20 paracetamol tablets used as a negative control., Results: We found that 32.9 µg and 49.5 µg of dexamethasone had been transferred to the suction cup in the two experiments. This is approximately 1 per mille of the dexamethasone content in a 40 mg tablet., Conclusion: We conclude that uncoated dexamethasone does shed measurable residue in the robot. It remains unknown to what extent this residue contaminates the subsequent production., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

SCO-101 (Endovion) was discontinued 20 years ago as a new drug under development against sickle cell anaemia. Data from the phase 1 studies remained unpublished. New data indicate that SCO-101 might be efficacious as add-on therapy in cancer. Thus, we report the results from the four phase 1 trials performed between 2001 and 2002. Adult volunteers received SCO-101 or placebo in four independent trials. Adverse events were recorded, and SCO-101 was determined for pharmacokinetic analysis. Ninety-two volunteers completed the trials. The most remarkable adverse effect was a transient and dose-dependent increase in unconjugated bilirubin. Plasma SCO-101 elimination was approximately log linear, with apparent oral clearances of between 315 and 2103 mL/h for single doses, and between 121 and 2433 mL/h at steady state following oral administration. There was a marked decrease in clearance with increasing dose, and for repeated dose versus single dose. T max was greater, and C max and AUC ∞ were lower in the fed state compared to the fasted state. Exposure was equivalent in males and females and for African Americans and Caucasians. In conclusion, SCO-101 appears to be a safe drug with a predictable PK profile. Its efficacy as add-on to standard anticancer drugs has yet to be defined., (© 2020 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial., Materials and Methods: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D)., Results: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21., Conclusions: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract the maximum concentration (C max ), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121 aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m 2 and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles. The most widely used dose of cremophor-diluted paclitaxel, 175 mg/m 2 given as a 3-h infusion, leads to an interstudy median C max of 5.1 µmol/L [interquartile range (IQR) 4.5-5.7], CL of 12.0 L/h/m 2 (IQR 10.9-12.9), and T > 0.05 µmol/L of 23.8 h (IQR 21.5-26.8). Importantly, the significant interindividual variation widely reported in the literature is not reflected in these interstudy estimates of pharmacokinetic parameters. Cremophor-diluted paclitaxel pharmacokinetics are non-linear following short (<6 h) but not long (>24 h) infusions. A similar pattern of non-linearity was observed for nab-paclitaxel, although the number of studies was limited. The pharmacokinetics of paclitaxel monotherapy have been widely studied at numerous dose levels of the Cremophor EL ® formulation, but are less well-characterized for the newer nab-paclitaxel formulation. In conclusion, paclitaxel pharmacokinetics are non-linear for short infusion times but not for longer infusions. Whether a similar conclusion can be drawn for nab-paclitaxel formulations requires further study.

Introduction: Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients., Methods: Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts., Results: It was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks (p = 0.0003) and 1 year, respectively (p < 0.0017), and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p < 0.05). Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target., Conclusion: This study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.

e-Cigarettes have gained worldwide popularity as a substitute for smoking, but concern has been raised regarding the long-term effects associated with their use. We report a case of a 45-year-old female consumer of e-cigarettes who presented with 4 months of abdominal pain and fever. Initial imaging discovered multiple pulmonary nodules and liver lesions suspicious of widespread metastases; however, an extensive evaluation found no evidence of malignancy. Results of a lung biopsy revealed an area with multinucleated giant cells suggestive of a foreign body reaction to a lipophilic material. Upon cessation of e-cigarette use (known as vaping), the lung nodules disappeared, and the liver lesions regressed. Our case report suggests that vaping can induce an inflammatory reaction mimicking metastatic cancer., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of the present case report was to describe a novel pharmacokinetic drug–drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel., Methods: The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-β-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry., Results: The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176–726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 μM clopidogrel acyl-β-D-glucuronide inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%., Conclusion: This is the first report of a clopidogrel–paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.

Background and Objective: Long-term adverse effects of oral glucocorticoids are frequent and serious. Large between-patient variability in the pharmacokinetics of prednisolone might explain why drug dose is a poor predictor of drug-related toxicity. The aim of the study was to investigate relationships between prednisolone exposure and adverse effects., Methods: Male kidney transplant recipients were recruited for serial blood sampling and assessment of glucocorticoid-related adverse effects including dyslipidaemia, abnormal body fat distribution, Cushingoid appearance and impaired quality of life. Total and free prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography with tandem mass spectrometric detection. Prednisolone exposure was estimated using a limited sampling strategy., Results: Fifty-six patients were recruited. Patients had a mean age of 54 years and median time post-transplantation of 75 months. Median prednisolone dose was 5 mg. Mean area under the plasma concentration-time curve was 2390 nmol h/L (±580) (SD) and 175 nmol h/L (±78) for total and free prednisolone, respectively. Waist to upper arm circumference ratio was positively associated with free prednisolone plasma exposure with a Spearman correlation coefficient of 0.30 (p value 0.02). The correlation coefficient was 0.24 (p value 0.08) for neck to upper arm circumference ratio and free prednisolone plasma exposure. The clinical Cushingoid phenotype as determined by the Visual Assessment of Cushing's Severity (VACS) score was associated with a reduced score relating to physical functioning on the SF-12, but there was no significant relationship between free prednisolone plasma exposure and quality-of-life scores. Lipid levels and haemoglobin A1c (HbA1c) were not associated with total or free prednisolone exposure., Conclusions: There is a positive correlation between free prednisolone plasma exposure and waist to upper arm circumference ratio in adult male kidney transplant recipients on low maintenance prednisolone doses. There is no significant association between total or free prednisolone plasma exposure and plasma glucose and lipid levels in the low prednisolone dose range.

Background: Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN., Material and Methods: DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two polymorphisms in GSTP1 and three in ABCB1 were selected for the primary analysis, and a host of other candidate genes was explored and compared between 75 patients with clinician-reported DIPN grade ≥ 2 and 75 patients without DIPN., Results: Patients with the genetic variants GSTP1 rs1138272 C/T or T/T (114Ala/114Val or 114Val/114Val) genotype had an adjusted odds ratio of 3.82; 95% confidence interval 1.34-11.09 of developing DIPN. This result was confirmed in both analysis of cumulated docetaxel dose and haplotype analysis. None of the explorative genes investigated were significantly correlated with DIPN. Patients with a BMI ≥ 30 were five-fold more likely to have DIPN than patients with BMI < 25., Conclusion: We found that GSTP1 Ala114Val polymorphism is associated with occurrence of DIPN. This supports the theory that oxidative stress is involved in DIPN pathophysiology. If confirmed, this may be helpful in the risk assessment of DIPN and perhaps help to achieve better management of neurotoxicity.

Aim: The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel-induced neuropathy but the data hitherto published are conflicting., Materials & Methods: In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic properties of CYP2C8.3 variant were analyzed using heterologous mammalian HEK293 cell expression system., Results: No significant association between CYP2C8*3 allele and neuropathy was found, although a trend was observed. The paclitaxel and amodiaquine metabolism by CYP2C8.3 were found similar to CYP2C8.1, whereas CYP2C8.3 was more efficient in the metabolism of rosiglitazone., Conclusion: These results indicate a difference in substrate specificity between CYP2C8.1 and CYP2C8.3; however, the CYP2C8*3 allele has no major impact on paclitaxel metabolism in vitro or of paclitaxel-induced neuropathy in vivo. Original submitted on 6 February 2015; revision submitted on 9 April 2015.

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., Results: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range., Conclusion: A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Background: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment., Methods: In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated., Results: Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09)., Conclusions: Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.

Background and Objective: Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus., Methods: Adult male kidney transplant recipients treated with prednisolone and either cyclosporine or tacrolimus were recruited for pharmacokinetic blood sampling at the outpatient clinic at the Princess Alexandra Hospital, Brisbane, Australia. Prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography. Dose-adjusted area under the plasma concentration-time curve (AUC) of free and total prednisolone was estimated using a previously developed limited sampling strategy and non-compartmental analysis., Results: A total of 55 patients were eligible for analysis; 38 % received cyclosporine and 62 % received tacrolimus co-therapy. No significant difference in mean dose-adjusted total prednisolone AUC from 0 to 6 h post-dose or mean dose-adjusted free prednisolone AUC from 0 to 12 h was observed between the cyclosporine and tacrolimus groups (449 versus 428 nmol·h/L/mg, p = 0.43, and 32 versus 30 nmol·h/L/mg, p = 0.51, respectively)., Conclusion: Cyclosporine does not change the dose-adjusted exposure of prednisolone compared with tacrolimus. Adult kidney transplant recipients can therefore continue on their usual prednisolone dose when changing therapy between cyclosporine and tacrolimus.

Objectives: The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation., Methods: Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled., Results: Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively., Conclusions: In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.

Background: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body., Aim: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients., Methods: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies., Results: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure., Conclusions: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.

Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant recipients is evident. Time post-transplant, hepatic and renal dysfunction, patient age, sex, bodyweight, serum albumin concentration, concomitant medication exposure, various disease states and genetic polymorphisms in metabolic enzymes and drug transporters have sometimes been associated with prednisolone pharmacokinetic variability. The clinical impact of corticosteroid therapy on the disposition of ciclosporin, tacrolimus and sirolimus and the impact of different immunosuppressant therapy combinations on prednisolone exposure needs to be further elucidated. Patient response patterns to prednisolone are consistent with delayed and indirect mechanisms of corticosteroid action involving modification of nuclear transcription and protein synthesis. Many adverse effects have been linked with prednisolone and prednisone therapy, but not all of these have been investigated thoroughly in transplant populations. Dyslipidaemia, growth restriction, diabetogenesis, hypertension and cataracts are well studied toxicities. Evidence is less clear for prednisolone-induced osteonecrosis, obesity and hypertriglyceridaemia. There have been some reports of a relationship between prednisolone pharmacokinetics and incidence of acute rejection, Cushing's syndrome and adverse cardiovascular and metabolic events. Dosing of prednisolone and prednisone in transplantation is typically empirical and varies significantly across transplant centres. Currently, authoritative guidelines are conflicting in their opinions regarding corticosteroid avoidance and early discontinuation in adult kidney transplantation. Overall, data suggest the promise of corticosteroid-free immunosuppression in paediatric patients. Further investigation of the pharmacokinetics and pharmacodynamics of prednisolone and prednisone in transplant recipients based on new chromatography assay techniques and free drug measurement, population pharmacokinetic/pharmacodynamic modelling approaches, genetic testing and larger studies in patients on modern day immunosuppressant protocols may lead to better individualization of corticosteroid therapy in the future.

The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T/A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

Purpose: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival., Methods: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis., Results: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival., Conclusion: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).

Purpose: To determine the distribution of clinically important CYP2C genotypes and allele frequencies in healthy Nordic populations with special focus on linkage disequilibrium., Methods: A total of 896 healthy subjects from three Nordic populations (Danish, Faroese, and Norwegian) were genotyped for five frequent and clinically important CYP2C allelic variants: the defective CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2C19*2 alleles, and the CYP2C19*17 allele that causes rapid drug metabolism. Linkage disequilibrium was evaluated and CYP2C haplotypes were inferred in the entire population., Results: Ten CYP2C haplotypes were inferred, the most frequent of which (49%) was the CYP2C wildtype haplotype carrying CYP2C8*1, CYP2C9*1, and CYP2C19*1. The second most frequent haplotype (19%) is composed of CYP2C19*17, CYP2C8*1, and CYP2C9*1. This predicted haplotype accounts for 99.7% of the CYP2C19*17 alleles found in the 896 subjects., Conclusion: CYP2C19*17 is a frequent genetic variant in Nordic populations that exists in strong linkage disequilibrium with wildtype CYP2C8*1 and CYP2C9*1 alleles, which effectively makes it a determinant for a haplotype exhibiting an efficient CYP2C substrate metabolism.

A case of hepatic abscesses due to Yersinia enterocolitica in an immunocompetent male is presented. Re-examination after 3 months showed that the patient had primary haemochromatosis. Treatment with repeated phlebotomies was instituted. Two years after the patient was first admitted to hospital. 17.2 g iron had been removed and all haematological and biochemical parameters had returned to normal. Genetic analysis of the patients' two sons showed that one was positive for the chromosome defect found in primary haemochromatosis; further investigation is under progress. A study of the literature showed that prior to this case only 45 cases of hepatic abscess secondary to Yersinia enterocolitica have been registered. Of the 45 reported cases, 64% had underlying haemochromatosis and 29% had diabetes mellitus. The overall mortality was 31%. Mortality before 1987 was 60% (n = 20) and since 1987 it has been 8% (n = 25).

Objective: Duplication of CYP2D6 causes very rapid metabolism of CYP2D6 substrates such as desipramine. However, we have previously shown that in the Danish population, only about 15% of very rapid metabolisers, defined as subjects with a metabolic ratio of sparteine of 0.15 or less, carried a duplicated allele. The question is whether gene duplication is a relatively rare cause (perhaps predictor) of very rapid metabolism or whether a low metabolic ratio is a poor predictor of this., Methods: After measuring metabolic ratios anew, we selected six volunteers with duplication of CYP2D6 and metabolic ratios ranging from 0.07 to 0.17 and six volunteers without duplication with metabolic ratios ranging from 0.08 to 0.21. Each subject took 100 mg of desipramine. Blood and urine were collected for 48 h., Results: The median total oral clearance of desipramine was 372 l/h and 196 l/h [median difference 108 l/h (95.9% c.i., -304-598 l/h)] and the median partial clearance of desipramine by 2-hydroxylation was 155 l/h and 87 l/h [median difference 47 l/h (95.9% c.i., -124-141 l/h)] for the group with duplication and the group without duplication, respectively., Conclusion: The predictive value of duplication of CYP2D6 is poor; there must be other causes (or predictors) of very rapid metabolism and with much higher frequency than duplication of CYP2D6.