Complex Relationships between Diagnostics and Survival in Chronic Lymphocytic Leukemia in Denmark, Finland, Norway, and Sweden.

Background: Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and we thus wanted to analyze age-specific survival trends through 50 years up to 2020s.

Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

Aims: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions.

Methods: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics.

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics.

Aims: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.

Methods: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).

Results: In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.

Genomewide Association Study of Simvastatin Pharmacokinetics.

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.

Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure.

Effect of High-Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long-lasting Inhibition of CYP2C19.

In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.

UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study.

To investigate how variability in multiple pharmacokinetic genes associates with telmisartan exposure, we determined telmisartan single-dose (40 mg) pharmacokinetics and sequenced 379 genes in 188 healthy volunteers. Intronic UGT1A variants showed the strongest associations with the area under the plasma concentration-time curve from zero hours to infinity (AUC ) and peak plasma concentration (C ) of telmisartan. These variants were strongly linked with the increased function UGT1A3*2 allele, suggesting that it is the causative allele underlying these associations.

Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction.

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics.

Enantiospecific Pharmacogenomics of Fluvastatin.

The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.

Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel.

Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.

To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10 ).

SLCO2B1 c.935G>A single nucleotide polymorphism has no effect on the pharmacokinetics of montelukast and aliskiren.

Objective: A nonsynonymous single nucleotide polymorphism (SNP) in the SLCO2B1 gene encoding organic anion transporting polypeptide 2B1 (OATP2B1), c.935G>A (p.R312Q; rs12422149), has been associated with reduced plasma concentrations of montelukast in patients with asthma.

Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren.

Aim: The aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.

Methods: In a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren.

Effect of ABCB1 haplotypes on the pharmacokinetics and renin-inhibiting effect of aliskiren.

Purpose: This study aimed to investigate the possible effects of ABCB1 haplotypes on the pharmacokinetics and renin-inhibiting effect of aliskiren.

Methods: Eleven healthy volunteers homozygous for the ABCB1 c.1236C-c.

Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren.

In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.

Rifampicin reduces the plasma concentrations and the renin-inhibiting effect of aliskiren.

Purpose: This study aimed to investigate the effect of rifampicin, an inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of aliskiren, a renin inhibitor used in the treatment of hypertension.

Methods: In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days. On day 6, they ingested a single 150-mg dose of aliskiren.